Arylpiperazinyl-cyclohexyl indole derivatives for the treatment of depression

ABSTRACT

Compounds are provided which are useful for the treatment of serotonin-affected neurological disorders which comprise  
                 
 
     Wherein:  
     R 1 , R 2  and R 3  are each, independently, hydrogen, halogen, CF 3 , alkyl, alkoxy, MeSO 2 , or together can form a 5-7 membered carbocyclic or heterocyclic ring;  
     R 4  is hydrogen, halogen, or alkyl;  
     R 5  is hydrogen, alkyl, alkylaryl, or aryl;  
     R 6  is hydrogen, halogen, CF 3 , CN, carbamide, or alkoxy;  
     X 1 , X 2  and X 3  are each carbon or one of X 1 , X 2  or X 3  may be nitrogen;  
     Y is carbon or nitrogen; and  
     Z is carbon or nitrogen; or  
     pharmaceutically acceptable salts thereof;

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/155,199, which was converted from U.S. patentapplication Ser. No. 09/226,583 filed Jan. 7, 1999.

FIELD OF INVENTION

[0002] This invention relates to compounds useful for the treatment ofdiseases affected by disorders of the serotonin-affected neurologicalsystems, such as depression and anxiety. More specifically the presentinvention is directed to arylpiperazinyl cyclohexyl derivatives usefulfor the treatment of such disorders.

BACKGROUND OF INVENTION

[0003] Pharmaceuticals which enhance neurotransmission of serotonin(5-HT) are useful for the treatment of many psychiatric disorders,including depression and anxiety. The first generation of non-selectiveserotonin-affecting drugs operated through a variety of physiologicalmeans which caused them to possess numerous undesired side-effects. Themore recently prescribed drugs, the selective serotonin reuptakeinhibitors (SSRIs), act predominately by inhibiting 5-HT, which isreleased at the synapses, from being actively removed from the synapticcleft via a presynaptic serotonin transport carrier. Since SSRIs requireseveral weeks before they exert their full therapeutic effect, this 5-HTblockade mechanism cannot fully account for their therapeutic activity.It is speculated that this two week induction which occurs before a fullantidepressant effect is observed, is due to the involvement of the5-HT1A autoreceptors which suppress the firing activity of 5-HT neurons,causing a dampening of the therapeutic effect. Studies suggest thatafter several weeks of SSRI administration, a desensitization of the5-HT autoreceptors occurs allowing a full antidepressant effect in mostpatients. (See, e.g., Le Poul et al., Arch. Pharmacol., 352:141 (1995)).Hence, it is believed that overriding this negative feedback by using5HT1A antagonists would potentially increase and accelerate the clinicalantidepressant response. Recent studies by Artigas et al., TrendsNeurosci., 19:378-383 (1996), suggest a combination of 5-HT1A activityand inhibition of 5-HT uptake within a single molecular entity canachieve a more robust and fast-acting antidepressant effect.

[0004] The present invention relates to a new class of molecules whichhave the ability to act at the 5-HT1A autoreceptors and concommitantlywith the 5-HT transporter. Such compounds are therefore potentiallyuseful for the treatment of depression as well as other serotonindisorders.

[0005] U.S. Pat. No. 5,468,767 reports a series of substituted indolesof the following formula for the treatment of disorders associated withdysfunction in serotonergic neurotransmission, including depression

[0006] wherein:

[0007] R₁ is hydrogen or C₁₋₄ alkyl and R₂ is C₁₋₄ alkyl or (CH₂)pAr.

[0008] WO 9415928 discloses a series of piperazine derivatives of thefollowing formula for the treatment of CNS disorders, includingdepression.

[0009] wherein:

[0010] R is hydrogen or alkyl;

[0011] R₁ and R₂ are each mono- or bicyclic aryl or heteroaryl radicals;

[0012] R₃ is hydrogen, alkyl, or a spirocycloalkyl group; and

[0013] n is 1 or 2 and m is 1 to 3.

[0014] WO 93/10092 discloses a series of cyclohexenes of the followingformula for the treatment of dopaminergic disorders.

SUMMARY OF THE INVENTION

[0015] The compounds of this invention are arylpiperazinyl-cyclohexylindole derivatives represented by Formula I:

[0016] Wherein:

[0017] R₁, R₂ and R₃ are each, independently, hydrogen, halogen, CF₃,alkyl, alkoxy, MeSO₂, or together can form a 5-7 membered carbocyclic orheterocyclic ring;

[0018] R₄ is hydrogen, halogen, or alkyl;

[0019] R₅ is hydrogen, alkyl, alkylaryl, or aryl;

[0020] R₆ is hydrogen, halogen, CF₃, CN, carbamide, or alkoxy;

[0021] X₁, X₂ and X₃ are each carbon or one of X₁, X₂ or X₃ may benitrogen;

[0022] Y is carbon or nitrogen; and

[0023] Z is carbon or nitrogen; or

[0024] pharmaceutically acceptable salts thereof.

[0025] Preferably, the compounds of the present invention are thoserepresented by Formula I, wherein R₁, R₂ and R₃ are each, independently,hydrogen, halogen, alkyl, alkoxy or together form a 5-7 memberedcarbocyclic or heterocyclic ring;

[0026] R₄ is hydrogen or halogen;

[0027] R₅ is hydrogen, alkyl or alkylaryl; and

[0028] R₆ is hydrogen, halogen, CN or alkoxy;

[0029] X₁, X₂, X₃, Y and Z are each carbon; or

[0030] pharmaceutically acceptable salts thereof.

[0031] More preferably, the compounds of the present invention areselected from the following:

[0032] 3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0033]3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0034]4-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0035]4-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0036]5-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0037]5-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0038]6-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0039]6-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0040]5-Bromo-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0041]5-Bromo-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0042]5-Chloro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0043] 5-Chloro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0044]3-{4-[(1,4-cis)-4-(1H-indol-4-yl)-piperazinyl-1-yl]cyclohexyl}-1H-indole-5-carbonitrile;

[0045]3-{4-[(1,4-trans)-4-(1H-indol-4-yl)-piperazinyl-1-yl]cyclohexyl}-1H-indole-5-carbonitrile;

[0046]5-Methoxy-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0047]5-Methoxy-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;

[0048]3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-2-methyl-1H-indole;

[0049]3-[trans-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-2-methyl-1H-indole;

[0050]3-{(1,4-cis)-4-[4-1H-Indole-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo[2,3-b]pyridine;

[0051]3-{(1,4-trans)-4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo[2,3-b]pyridine;

[0052]6-Fluoro-1-methyl-3-{cis-4-[4-(1-methyl-1H-indol-4-yl)-1-piperazinyl]cyclohexyl}-1H-indole;

[0053]3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-methyl-1H-indole-5-carbonitrile;

[0054]3-{(1,4-trans)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-methyl-1H-indole-5-carbonitrile;

[0055]1-Ethyl-3-{(1,4-cis)-4-[4-(1H-indole-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0056]3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1-propyl-1H-indole-5-carbonitrile;

[0057]3-{(1,4-trans)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl;}-1-propyl-1H-indole-5-carbonitrile;

[0058]3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1-isopropyl-1H-indole-5-carbonitrile;

[0059]3-{(1,4-trans)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-isopropyl-1H-indole-5-carbonitrile;

[0060]1-Benzyl-3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0061]1-Benzyl-3-{(1,4-trans)-4-[4-(1H-indole-4-yl)-piperazin-1-yl]cyclohexyl}-1H-indole-5-carbonitrile;

[0062]1-Methyl-3-{(1,4-cis)-4-[4-(1-methyl-1H-indol-4-yl)-piperazine-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0063]5-Fluoro-3-{(cis)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-indole;

[0064]5-Fluoro-3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-1H-indole;

[0065]5-Fluoro-3-{(1,4-trans)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-1H-indole;

[0066]5-methoxy-3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperazinyl-1-yl]-cyclohexyl}-1H-indole;

[0067]5-Methoxy-3-{(1,4-trans)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-1H-indole;

[0068]3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo[2,3-b]piperidine;

[0069]5-Fluoro-3-{(cis)-4-[4-(5-fluoro-2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-indole;

[0070]5-Fluoro-3-{(trans)-4-[4-(5-fluoro-2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-indole;

[0071]3-{(1,4-cis)-4-[4[(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-4-fluoro-1H-indole;

[0072]3-{(1,4-trans)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-4-fluoro-1H-indole;

[0073]3-{(1,4-cis)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-5-fluoro-1H-indole;

[0074]3-{(1,4-trans)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-5-fluoro-1H-indole;

[0075]3-{(1,4-cis)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-6-fluoro-1H-indole;

[0076]3-{(1,4-trans)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-6-fluoro-1H-indole;

[0077]3-{(1,4-trans)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-6-fluoro-1H-indole;

[0078]3-{(1,4-cis)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0079]3-{(1,4-trans)-4-(4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0080]8-{4-[(1,4-cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}quinoline;

[0081]8-{4-[(1,4-trans)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-quinoline;

[0082]8-{4-(1,4-cis)-4-[4-(5-Fluoro-1-methyl-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-quinoline;

[0083]3-[(1,4-cis)-4-(4-Quinolin-8-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-carbonitrile;

[0084]3-[(1,4-trans)-4-(4-Quinolin-8-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-carbonitrile;

[0085]1-Methyl-3-[(1,4-cis)-4-(4-quinolin-8-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-carbonitrile;

[0086]5-Fluoro-3-{(1,4-cis)-4-[4-(6-fluoro-chroman-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole;

[0087]5-Fluoro-3-{(1,4-trans)-4-[4-(6-fluoro-chroman-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole;

[0088]5-Fluoro-3-{(1,4-cis)-4-[4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole;

[0089]5-Fluoro-3-{(1,4-trans)-4-[4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole;

[0090]3-{(1,4-cis)-4-[4-(5-Fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0091]3-{(1,4-trans)-4-[4-(5-Fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0092]3-{(1,4-cis)-4-[4-(5-Fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1yl]-cyclohexyl}-1-methyl-1H-indole-5-carbonitrile;

[0093]3-[(1,4-cis)-4-[4-(Benzofuran-7-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-carbonitrile;

[0094]3-[(1,4-trans)-4-[4-(Benzofuran-7-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-carbonitrile;

[0095]5-Fluoro-3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]cyclohex-1-enyl}-1H-indole;

[0096]3-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-cyclohex-1-enyl}-1H-indole-5-carbonitrile;

[0097]5-Fluoro-3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1,3-dihydro-indol-2-one;

[0098]5-Fluoro-3-{cis-4-[4-(1H-indol-4-yl)piperazinyl]-cyclohexyl}-1-methyl-1H-indole;

[0099]8{(1,4-cis)-4-[4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-6-methoxy-quinoline;

[0100]8-{(1,4-trans)-4-[4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]piperazin-1-yl}-6-methoxy-quinoline;

[0101]3-{(1,4-cis)-4-[4-6-Methoxy-quinoline-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0102]3-{(1,4-trans)-4-[4-(6-Methoxy-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0103]6-Chloro-8-{4-[1,4-cis)-4-(5-fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}quinoline;

[0104]6-Chloro-8-{4-[(1,4-trans)-4-(5-fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}quinoline;

[0105]3-{(1,4-cis)-4-[(4-(6-Chloro-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0106]3-{(1,4-trans)-4-[4-(6-Chloro-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0107]5-Chloro-8-{4-[(1,4-cis)-4-(5-fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-quinoline;

[0108]3-{(1,4-cis)-4-[4-(5-Chloro-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0109]5-Fluoro-8-{4-[(1,4-cis)-4-(6-fluoro-1H-indole-3-yl)-cyclohexyl]-piperazin-1-yl}-quinoline;

[0110]5-Fluoro-8-{4-[(1,4-trans)-4-(6-fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-quinoline;

[0111]3-{(1,4-cis)-4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0112]3-{(1,4-trans)-4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0113]4-{4-[(1,4-cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-2-trifluoromethyl-quinoline;

[0114]4-{4-[(1,4-trans)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-2-trifluoromethyl-quinoline;

[0115]3-{(1,4-cis)-4-[4-(2-Trifluoromethyl-quinolin-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile

[0116]3-{(1,4-trans)-4-[4-(2-Trifluoromethyl-quinolin-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;

[0117]4-{4-[(1,4-cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-6-methoxy-quinoline;

[0118]4-{4[(1,4-trans)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-6-methoxy-quinoline;

[0119]3-{(1,4-cis)-4-[4-(6-Methoxy-quinolin-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;and

[0120]3-{(1,4-trans)-4-[4-(6-Methoxy-quinolin-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile.

[0121] As used herein, the terms “alkyl” and “alkoxy” are meant toinclude both straight and branched carbon chains containing 1-6 carbonatoms. The term “aryl” is meant to include aromatic radicals of 6-12carbon atoms. The term “halogen” is meant to include fluorine, chlorine,bromine and iodine.

[0122] The compounds of Formula I also may be used in the form of apharmaceutically acceptable acid addition salt having the utility of thefree base. Such salts, prepared by methods well known to those skilledin the art are formed with both inorganic or organic acids, for example:fumaric, maleic, benzoic, ascorbic, pamoic, succinic,bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic,malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic,itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic,hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric andnitric acids.

[0123] The compounds of the present invention may be prepared by anysuitable method which will be recognized by those skilled in the art.However, the present compounds may be advantageously prepared accordingto any one of Schemes 1-6 set forth below. In the Schemes, theintermediate compounds exemplified hereinafter are identified inparenthesis. The compound produced in each of Schemes 1-6 is identifiedwith reference to the appropriate Example set forth below.

[0124] The preparation of such compounds is depicted in Schemes 1-6below.

[0125] The following Schemes 37-39 were utilized to obtain the compoundsof Examples 86-114.

INTERMEDIATE 1 3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole (1a)

[0126] Indole (4.69, 40 mmol), 1,4-cyclohexanedione monoethylene ketal(6.3 g, 40 mmol) and potassium hydroxide (13.2 g, 200 mmol) were heatedto reflux in 70 ml methanol for 6 hours. The reaction was cooled and theproduct was isolated by filtration and washed with water to give 9.1 g(89%) of product.

3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-4-fluoro-1H-indole (1b)

[0127] This compound was prepared in a similar fashion described aboveby replacing indole with 4-fluoroindole (3 g, 22 mmol) to afford thetitle compound in quantitative yield as a white solid: mp at 140° C.(sublimated).

3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-5-fluoro-1H-indole (1c)

[0128] 5-Fluoroindole (4.96 g, 0.036 mol), 1,4-cyclohexanedionemonoethylene ketal (7.17 g, 0.046 mol) and potassium hydroxide (6 g, 91mmol) were heated to reflux in 70 ml methanol for 6 hours. The reactionwas cooled and the product was isolated by filtration and washed withwater to give 8.59 g (86%) of product as a white solid: mp 153-155° C.

3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-6-fluoro-1H-indole (1d)

[0129] This compound was prepared in the manner described forintermediate 1a by replacing indole with 6-fluoroindole (5.14 g, 38mmol) ) to afford 10 g (96.3%) of the title compound as a white solid:mp 196-197° C.

[0130] Elemental analysis for C₁₆H₁₆FNO₂ Calc'd: C, 70.32; H, 5.90; N,5.13 Found: C, 70.62; H, 5.91; N, 5.08

3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-5-bromo-1H-indole (1e)

[0131] This compound was prepared in the manner described above forintermediate 1a by replacing indole with 5-bromoindole (7.84 g, 40 mmol)) to afford 10.5 g (78%) of the title compound as a white solid; MS EIm/e 333 (M⁺).

3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-5-chloro-1H-indole (1f)

[0132] This compound was prepared in the manner described above forintermediate 1a by replacing indole with 5-chloroindole (5 g, 33 mmol) )to afford 9.14 g (96%) of the title compound as a white solid: mp178-181° C.; MS EI m/e 273 (M⁺).

3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-5-cyano-1H-indole (1g)

[0133] This compound was prepared in the manner described above forintermediate 1a by replacing indole with 5-cyanoindole (29.98 g, 0.21mol) to afford 29.32 g (50%) of the title compound as a white solid: mp158-160° C.

3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-5-methoxy-1H-indole (1h)

[0134] This compound was prepared in the manner described above forintermediate 1a by replacing indole with 5 methoxy indole (5 g, 34 mmol)in 82% yield (7.95 g) as a white solid: mp 161-162° C.

3- (1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-2-methyl-1H-indole (1i)

[0135] A solution of 2-methyl-indole (2.0 g, 15.2 mmol),1,4-cyclohexanedione monoethylene ketal (4.76 g, 30.4 mmol) andpotassium hydroxide (10 g, 0.18 mol) were heated to reflux in 50 mlmethanol for 48 hours. The mixture was poured into water (150 ml) andextracted with methylene chloride (2×200 ml). The organic layer wasdried over anhydrous magnesium sulfate, filtered, and solvent wasremoved under vacuum. Chromatography (25% ethyl acetate-hexanes)afforded a light tan solid which was washed with ethyl ether (20 ml) toafford 2.35 g (62%) of product as a white solid: mp 136-137° C.

[0136] Elemental analysis for C₁₇H₁₉NO₂ Calc'd: C, 75.81; H, 7.11; N,5.70 Found: C, 75.47; H, 7.26; N, 5.13

3-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-1H-azaindole (1j)

[0137] This compound was prepared in the manner described above forintermediate 1a by replacing indole with 7-azaindole (3.65 g, 31 mmol)in 68% yield (5.42 g) as a white solid: mp 162-165° C.; MS EI m/e 256(M⁺).

INTERMEDIATE 2 3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-1H-indole (2a)

[0138] A mixture of 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole (8.0g, 31.3 mmol) and 10% palladium on carbon (1.3 g) in ethanol (700 ml)was hydrogenated for 18 hours. The catalyst was filtered off and thesolvent removed under vacuum to afford 8.01 g (99%) of product as awhite solid.

3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-4-fluoro-1H-indole (2b)

[0139] This compound was prepared in the manner described above forintermediate 2a by replacing3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole with3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-4-fluoro-1H-indole (6.3 g) ) toafford 4.44 g (70%) of the title compound as a white solid: mp 161-162°C.

[0140] Elemental analysis for C₁₆H₁₈FNO₂ Calc'd: C, 69.08; H, 6.59; N,5.09 Found: C, 69.05; H, 6.56; N, 4.87

3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-fluoro-1H-indole (2c)

[0141] A mixture of of3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-fluoro-1H-indole (8.5 g) and 10%palladium on carbon (2.72 g) in ethanol (200 ml) was hydrogenated for 5hours. The catalyst was filtered off and the solvent removed undervacuum. Chromatography (methanol-methylene chloride) afforded 7.55 g(82%) of product as a white solid: mp 183-185° C.

3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-6-fluoro-1H-indole (2d)

[0142] This compound was prepared in the manner described above forintermediate 2a by replacing3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole with3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-6-fluoro-1H-indole (9.54 g) toafford 5.83 g (60%) of the title compound as a white solid: mp 158-159°C.

[0143] Elemental analysis for C₁₆H₁₈FNO₂ Calc'd: C, 69.80; H, 6.59; N,5.09 Found: C, 69.74; H, 6.48; N, 5.13

3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-bromo-1H-indole (2e)

[0144] A mixture of3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-bromo-1H-indole (6.8 g, 20.34mmol) and 5% platinum on carbon (5.0 g) in ethanol (500 ml) washydrogenated overnight. The catalyst was filtered off and the solventremoved under vacuum. Chromatography (30% ethyl acetate-hexanes)afforded 5.0 g (73%) of product as a solid; MS EI m/e 336 (M⁺).

3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-chloro-1H-indole (2f)

[0145] A mixture of3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-chloro-1H-indole (0.18 g) andplatinum oxide (0.02 g) in ethanol (20 ml) with ten drops of acetic acidwas hydrogenated overnight. The catalyst was filtered off and thesolvent removed under vacuum. Chromatography (25% ethyl acetate-hexanes)afforded 0.16 g (88%) of product as a white solid: mp 205-206.5° C.

3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-cyano-1H-indole (2g)

[0146] This compound was prepared in the manner described above forintermediate 2a by replacing3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole with3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-cyano-1H-indole (54.6 g) ) toafford 52.12 g (95%) of the title compound as a white solid in 95%(52.12 g) yield as a white solid: mp 153-155° C.

3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-methoxy-1H-indole (2h)

[0147] This compound was prepared in the manner described above forintermediate 2a by replacing3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole with3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-methoxy-1H-indole to afford 7.18g (96%) of the title compound as a white solid: mp 153-155° C.

3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-2-methyl-1H-indole (2i)

[0148] A mixture of3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-2-methyl-1H-indole (2.39 g, 8.9mmol) and 10% palladium on carbon (0.35 g) in ethanol (80 ml) washydrogenated for 3 hours. The catalyst was filtered off and then asolution of methylene-methanol (80 ml) was used to dissolve any solidswithin the celite. The solvent removed under vacuum to afford 2.34 g(97%) of product as an off-white solid, which was triturated with ethylether (40 ml) to afford a white solid: mp 166-168° C. The mother liquorwas concentrated to afford another 1.2 g of product as a yellow solid.

[0149] Elemental analysis for C₁₇H₂₁NO₂ Calc'd: C, 75.25; H, 7.80; N,5.16 Found: C, 75.17; H, 7.99; N, 5.12

3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-1H-azaindole (2j)

[0150] This compound was prepared in the manner described above forintermediate 2a by replacing3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole (7.18 g) with3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-azaindole (4.02 g) to afford2.7 g (67%) of the title compound as a white solid: mp 204-207° C.

[0151] Elemental analysis for C₁₃H₁₄N₂O Calc'd: C, 72.87; H, 6.59; N,13.07 Found: C, 72.44; H, 6.75; N, 12.81

INTERMEDIATE 3 4-(1H-3-Indolyl)-cyclohexanone (3a)

[0152] A solution of 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole (2.57 g,10 mmol) in 200 ml (1:1) tetrahydrofuran-hydrochloric acid (1N) wasallowed to stir at room temperature for 16 hours. The solvent wasevaporated under vacuum. The crude product was dissolved in ethylacetate, washed with 1N sodium hydroxide (3×150 ml). The organic layerwas dried over anhydrous sodium sulfate, and filtered. Chromatography(40% ethyl acetate-hexanes) afforded 1.9 g (89%) of product.

4-(4-Fluoro-1H-3-indolyl)-cyclohexanone (3b)

[0153] This compound was prepared in the manner described above for 3aby replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole with3-(1,4-dioxa-spiro[4,5]dec-8-yl)-4-fluoro-1H-indole (4.0 g) to afford3.7 g (63%) of the title compound as a white solid: mp 104-106° C.

4-(5-Fluoro-1H-3-indolyl)-cyclohexanone (3c)

[0154] A solution of 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-fluoro-1H-indole(2.8 g, 10 mmol) in 200 ml(1:1) tetrahydrofuran-hydrochloric acid (1N)was allowed to stir at room temperature for 16 hours. The solvent wasevaporated under vacuum. The crude product was dissolved in ethylacetate, washed with 1N sodium hydroxide (3×150 ml). The organic layerwas dried over anhydrous sodium sulfate, and filtered. Chromatography(40% ethyl acetate-hexanes) afforded 2.1 g (91%) of product as yellowsolid: mp 112-114° C.

4-(6-Fluoro-1H-3-indolyl)-cyclohexanone (3d)

[0155] This compound was prepared in the manner described above forintermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indolewith 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-6-fluoro-1H-indole (5.4 g) toafford 19.29 g (99%) of the title compound as a white solid: mp 102-105°C.

[0156] Elemental analysis for C₁₄H₁₄NOF Calc'd: C, 72.71; H, 6.10; N,6.06 Found: C, 72.77; H, 5.98; N, 5.96

4-(5-Bromo-1H-3-indolyl)-cyclohexanone (3e)

[0157] This compound was prepared in the manner described above forintermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indolewith 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-bromo-1H-indole (4.5 g) toafford 3.3 g (84%) of the title compound as a white solid: MS EI m/e 291(M⁺).

[0158] Calc'd: C, 75.25; H, 7.80; N, 5.16 Found: C, 75.17; H, 7.99; N,5.12

4-(5-Chloro-1H-3-indolyl)-cyclohexanone (3f)

[0159] This compound was prepared in the manner described above forintermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indolewith 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-chloro-1H-indole (2.12 g) toafford 1.13 g (60%) of the title compound as a clear oil: MS FAB m/e 248(M+H)⁺.

4-(5-Cyano-1H-3-indolyl)-cyclohexanone (3g)

[0160] This compound was prepared in the manner described above forintermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indolewith 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1H-indole (6 g) to afford4.03 g (81%) of the title compound as a white solid: mp 162.5-164° C.

[0161] Elemental analysis for C₁₅H₁₄N₂O Calc'd: C, 75.61; H, 5.92; N,11.76 Found: C, 75.82; H, 6.06; N, 11.72

4-(5-Methoxy-1H-3-indolyl)-cyclohexanone (3h)

[0162] This compound was prepared in the manner described above forintermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indolewith 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-methoxy-1H-indole (5.85 g) toafford 4.2 g (85%) of the title compound as a white solid: mp 103-106°C.

4-(2-Methyl-1H-3-indolyl)-cyclohexanone (3i)

[0163] This compound was prepared in the manner described above forintermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indolewith 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-2-methyl-1H-indole (2.2 g) toafford 1.62 g (88%) of the title compound as a yellow thick oil: MS EIm/e 227 (M⁺).

4-(1H-3-pyrrolo[2,3-b]pyridyl)-cyclohexanone (3j)

[0164] This compound was prepared in the manner described above forintermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indolewith 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-azaindole (2.48 g) to afford1.96 g (95%) of the title compound as a white solid: mp 162-164° C.

INTERMEDIATE 43-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-5-cyano-1-methyl-indole

[0165] To a suspension of sodium hydride (60%, 1.74 g, 0.073 mol) inanhydrous N,N-dimethylformamide (100 ml) was added3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-cyano-1H-indole (9.9 g, 0.035mol) at room temperature. The mixture was stirred for 30 minutes at roomtemperature, then methyl iodide (9 ml, 0.14 mol) was added at roomtemperature. The reaction was allowed to stir for 1 hour, then quenchedwith water (50 ml). The mixture was extracted with methylene chloride(3×150 ml) and water (3×150 ml). The organic layer was dried overanhydrous magnesium sulfate and filtered. The solvent was removed undervacuum. Chromatography (5% methanol-methylene chloride) afforded 2.54 g(24%) of product as a light yellow solid: mp 65-67° C.

[0166] Elemental analysis for C₁₈H₁₈N₂O₂ Calc'd: C, 73.45; H, 6.16; N,9.52 Found: C, 73.17; H, 6.24; N, 9.43

INTERMEDIATE 5 3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-indole(5a)

[0167] A mixture of3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-bromo-1H-indole (3.77 g) and 10%palladium on carbon (0.99 g) in ethanol-tetrahydrofuran (200:80 ml) washydrogenated for 5 hours. The catalyst was filtered off and the solventwas removed under vacuum to afford a white powder which was washed withethanol-hexanes (1:1) and dried under vacuum for 4 hours to afford 2.75g (12%) of product: mp 170-172° C.

[0168] Elemental analysis for C₁₈H₂₀N₂O₂ Calc'd: C, 72.95; H, 6.80; N,9.45 Found: C, 72.79; H, 6.82; N, 9.35

3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-ethyl-indole (5b)

[0169] To a suspension of sodium hydride (60%, 1.63 g, 0.068 mol) inanhydrous N,N-dimethylformamide (150 ml) was added3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1H-indole (9.0 g, 0.032 mol) atroom temperature. The mixture was stirred for 30 minutes at roomtemperature then ethylbromide (14.6 g, 0.13 mol) was added at roomtemperature. The reaction was allowed to stir for overnight, thenquenched with water (50 ml). The mixture was extracted with methylenechloride (3×150 ml) and water (3×150 ml). The organic layer was driedover anhydrous magnesium sulfate and filtered. The solvent was removedunder vacuum. Chromatography (hexanes) afforded 5.5 g (69%) of productas a white solid: mp 124-126° C.

[0170] Elemental analysis for C₁₉H₂₂N₂O₂ Calc'd: C, 73.52; H, 7.14; N,9.02 Found: C, 73.56; H, 6.93; N, 8.95

3-(1,4-Dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-n-propyl-indole (5c)

[0171] This compound was prepared in the manner described above forintermediate 5b by replacing ethylbromide with n-propylbromide (13.1 g,11 mmol) to afford 4.33 g (75%) of the title compound as a oil: MS EIm/e 324 (M⁺).

3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-iso-propyl-indole (5d)

[0172] This compound was prepared in the manner described above forintermediate 5b by replacing ethylbromide with isopropylbromide (10.2 g,83 mmol) in 62% yield (6.44 g) as a white solid: mp 114.5-116° C.; MS EIm/e 324 (M⁺).

3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-benzyl-indole (5e)

[0173] This compound was prepared in the manner described above forintermediate 5b by replacing ethylbromide with benzylbromide (14.3 g, 84mmol) to afford 6.04 g (57%) of the title compound as a white solid: mp129-130° C.

[0174] Elemental analysis for C₂₃H₂₄N₂O₂ Calc'd: C, 77.39; H, 6.50; N,7.52 Found: C, 76.59; H, 6.28; N, 7.47

INTERMEDIATE 6 4-(5-Cyano-1-methyl-3-indolyl)-cyclohexanone (6a)

[0175] A solution of3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-indole (5.5 g) in 150ml (1:1) tetrahydrofuran-hydrochloric acid (1N) was allowed to stir atroom temperature for 16 hours, followed by the addition of 4.49 g sodiumbicarbonate. The mixture was extracted with methylene chloride (3×100ml), washed with brine (3×150 ml). The organic layer was dried overanhydrous magnesium sulfate and filtered. The solvent was removed toafford a light brown solid which was boiled in ethyl acetate-hexanes(1:1). The mixture was cooled to room temperature and solid wascollected and dried under vacuum to afford 2.06 g of the title compoundas a solid: mp 150-152° C.

[0176] Elemental analysis for C₁₅H₁₅N₂O Calc'd: C, 76.16; H, 6.39; N,11.10 Found: C, 75.84; H, 6.34; N, 10.92

4-(5-Cyano-1-ethyl-3-indolyl)-cyclohexanone (6b)

[0177] This compound was prepared in the manner described above forintermediate 6a by replacing3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-indole with3-(1,4-dioxa-spiro[4,5]-dec-8-yl)-5-cyano-1-ethyl-indole (6.77 g, 22mmol) to afford 4.33 g (75%) of the title compound as a white solid: mp124° C.

[0178] Elemental analysis for C₁₇H₁₈N₂O Calc'd: C, 76.66; H, 6.81; N,10.52 Found: C, 76.30; H, 6.82; N, 10.25

4-(5-Cyano-1-n-propyl-3-indolyl)-cyclohexanone (6c)

[0179] This compound was prepared in the manner described above forintermediate 6a by replacing3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-indole with3-(1,4-dioxa-spiro[4,5]-dec-8-yl)-5-cyano-1-n-propyl-indole (2.64 g, 8.2mmol) to afford 1.67 g (73%) of the title compound as a white solid: mp103-104° C.; MS EI m/e 280 (M⁺).

4-(5-Cyano-1-benzyl-3-indolyl)-cyclohexanone (6d)

[0180] This compound was prepared in the manner described above forintermediate 6a by replacing3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-indole with3-(1,4-dioxa-spiro[4,5]-dec-8-yl)-5-cyano-1-benzyl-indole (6.43 g, 20mmol) to afford 3.49 g (63%) of the title compound as a white solid: mp115-126° C.

[0181] Elemental analysis for C₂₂H₂₀N₂O Calc'd: C, 80.46; H, 6.14; N,8.53 Found: C, 80.42; H, 6.07; N, 8.49

4-(5-Cyano-1-isopropyl-3-indolyl)-cyclohexanone (6e)

[0182] This compound was prepared in the manner described above forintermediate 6a by replacing3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-indole with3-(1,4-dioxa-spiro[4,5]-dec-8-yl)-5-cyano-1-isopropyl-indole (5.86 g, 16mmol) to afford 3.46 g (63%) of the title compound as a white solid: mp106-107° C.

[0183] Elemental analysis for C₁₈H₂₀N₂O Calc'd: C, 77.11; H, 7.19; N, 9.Found: C, 76.85; H, 7.16; N, 9.

INTERMEDIATE 7 8-(4-Benzyl-piperazin-1-yl)quinoline

[0184] A solution of 8-amino-quinoline (12.91 g, 89 mmol) andbis(2-chloroethyl)-benzylamine (25.95 g, 112 mmol) in n-butanol (65 ml)was allowed to heat at 85° C. for 11 hours. The mixture was poured into50% sodium hydroxide, extracted with methylene chloride and water. Theorganic layer was dried over anhydrous magnesium sulfate, and filtered.The solvent was removed under vacuum. Chromatography (methanol-methylenechloride) afforded 12.34 g of product as a solid: mp 116.5-118° C.

[0185] The HCl salt was prepared in ethyl acetate: mp 209-210° C.

[0186] Elemental analysis for C₂₀H₂₁N₃.2HCl.0.5H₂O Calc'd: C, 62.34; H,6.28; N, 10.91 Found: C, 62.37; H, 6.55; N, 10.80

INTERMEDIATE 8 8-(Piperazin-1-yl)-quinoline

[0187] To a solution of 8-(4-benzyl-piperazin-1-yl)quinoline (2.63 g,8.7 mmol) in methylene chloride (30 ml) was added vinyl chloroformate(1.1 ml, 13 mmol) at room temperature slowly. The reaction mixture wasrefluxed for 2 hours, and then concentrated under vacuum. The residuewas dissolved in 12 N hydrochloric acid (20 ml) and stirred at roomtemperature for 1 hour. The mixture was concentrated, the residue wastaken up with 40 ml ethanol and heated up to 50° C. for 2 hours. Thesolvent was removed under vacuum, the residue was dissolved in 1 Nsodium hydroxide-ethyl acetate and extracted with ethyl acetate andwashed with water. The organic layer was dried over anhydrous sodiumsulfate. The solvent was removed under vacuum. Chromatography (10-30%methanol -methylene chloride plus ammonium hydroxide) afforded 1.86 g(90%) yellow oil; MS EI m/e 213 (M)⁺.

INTERMEDIATE 9 6-Fluorochroman

[0188] A mixture of 6-fluoro-4-oxo-chroman (2 g, 12 mmol) and 10%palladium on carbon (1 g) in concentrated hydrochloric acid (20 ml) andethanol (30 ml) was hydrogenated for 20 hours. The catalyst was filteredand the solvent removed under vacuum. The residue was dissolved in ethylacetate (100 ml), washed with 1N NaOH (6×200 ml) and water (3×150 ml),dried over anhydrous sodium sulfate, filtered and the solvent wasremoved under vacuum. Chromatography (20% ethyl acetate-hexanes)afforded 1.41 g (77%) of product as a clear oil; MS EI m/e 152 (M⁺).

INTERMEDIATE 10 6-Fluoro-8-nitrochroman

[0189] A mixture of nitric acid (100%, 7.8 ml, 0.16 mol) in aceticanhydride was maintained at room temperatue for 0.5 hour. This mixturewas added to a solution of 6-fluorochroman (11.9 g, 0.078 mol) in 40 mlacetic anhydride at 0° C. The reaction mixture was stirred at roomtemperature for 2 hours then poured into ice-water. The mixture wasextracted with methylene chloride (3×60 ml) and washed with saturatedsodium carbonate (8×150 ml). The organic layer was dried over anhydroussodium sulfate and filtered. The solvent was removed under vacuum toafford a yellow solid: mp 48-50° C.

[0190] Elemental analysis for C₉H₈FNO₃ Calc'd: C, 54.83; H, 4.09; N,7.10. Found: C, 54.78; H, 3.93; N, 6.09

INTERMEDIATE 11 6-Fluoro-8-aminochroman

[0191] A mixture of 6-fluoro-8-nitrochroman (14.4 g) and 10% palladiumon carbon (2 g) in ethanol (160 ml) was hydrogenated for 2 hours. Thecatalyst was filtered off and the solvent removed under vacuum.Chromatography (30% ethyl acetate-hexanes) afforded 12.12 g (100%) ofproduct as a clear oil; MS EI m/e 167 (M⁺).

INTERMEDIATE 12 1-Benzyl-4-(6-fluoro-chroman-8-yl)-piperazine

[0192] A solution of 6-fluoro-8-aminochroman (1.24 g, 7.4 mmol) andbis(2-chloroethyl)-benzylamine (2.58 g, 11 mmol) in butanol (20 ml) wasstirred at 100° C. for 10 hours. The mixture was poured into saturatedsodium carbonate (950 ml) and extracted with ethyl acetate (3×60 ml).The organic layer was dried over anhydrous sodium sulfate and filtered.Chromatography (20% ethyl acetate-hexanes) afforded 1.64 g (68%) ofproduct as an oil; MS EI m/e 326 (M)⁺.

INTERMEDIATE 13 4-(6-Fluoro-chroman-8-yl)-piperazine

[0193] A mixture of 1-benzyl-4-(6-fluoro-chroman-8-yl)-piperazine (1.64g, 5 mmol), 10% palladium on carbon (0.4 g) and ammonium formate (0.64g, 10 mmol) in ethanol (20 ml) was allowed to refux for 2 hours. Thecatalyst was filtered off and the solvent removed under vacuum.Chromatography (10-20% methanol-methylene chloride plus ammoniumhydroxide) afforded 1.0 g (84%) of product as a yellow oil; MS EI m/e296 (M⁺).

INTERMEDIATE 14 2-(4-Fluorophenoxy)-acetaldehyde diethyl acetal

[0194] To a suspension of sodium hydride (5.4 g, 0.134 mol) in anhydrousN,N-dimethylformamide (100 ml) was added 4-fluorophenol (10 g, 0.089mol) at 0° C. After hydrogen evolution had ceased, bromo-acetaldehydediethyl acetal (16 ml, 0.11 mol) was added. The reaction was heated at160-170° C. for 18 hours. The mixture was poured into ice-water,extracted with ethyl acetate (3×150 ml), washed with 1N sodium hydroxide(3×100 ml), and brine (3×100 ml). The organic layer was dried overanhydrous sodium sulfate and filtered. The solvent was removed undervacuum. Chromatography (25% ethyl acetate-hexanes) afforded 16.36 g(80%) of product as a clear oil: MS EI m/e 228 (M⁺).

INTERMEDIATE 15 5-Fluorobenzofuran

[0195] To a mixture of benzene (200 ml) containing polyphosphoric acid(7.9 g, 0.035 mol) was added 2-(4-fluoro-phenoxy)-acetaldehyde diethylacetal (8 g, 0.035 mol). The mixture was stirred vigorously while beingheated to reflux for 2.5 hours. The reaction mixture was cooled to roomtemperature and decanted from the polyphosphoric acid. The solvent wasremoved under vacuum. Chromatography (5% ethyl acetate-hexanes) afforded3.4 g (45%) of product as a clear oil: ¹H NMR (CDCl₃) δ 6.74 (dd, 1H,J=2.0, 0.6 Hz), 7.01 (td, 1H, J=9, 2.7 Hz), 7.25 (dd, 1H, J=8.4, 2.7Hz), 7.43 (dd, 1H, J=9, 3.9 Hz), 7.65 (d, 1H, J=1.8 Hz).

INTERMEDIATE 16 5-Fluoro-2,3-dihydrobenzofuran

[0196] A solution of 5-fluorobenzofuran and 10% palladium on carbon inacetic acid (25 ml) was hydrogenated under 50 psi for 12 hours. Thecatalyst was filtered through celite and the celite was washed withmethylene chloride (200 ml). The organic layer was washed sequentiallywith 1N NaOH (3×100 ml), brine (3×100 ml) and dried over anhydroussodium sulfate and filtered. The solvent was removed under vacuum toafforded 2.59 g (85%) of product as a clear oil: ¹H NMR (300 MHz,CDCl₃): δ 3.12 (t, 2H, J=8.7 Hz), 4.58 (t, 2H, J=8.7 Hz), 6.68 (dd, 1H,J=8.7, 4.2 Hz), 6.79 (tm, 1H, J=8.7 Hz), 6.89 (dm, 1H, J=8.1 Hz).

INTERMEDIATE 17 5-Fluoro-7-nitro-2,3-dihydrobenzofuran

[0197] A mixture of nitric acid (100%, 1.5 ml, 36 mmol) in aceticanhydride (18 ml) was maintained at room temperatue for 0.5 hour. Themixture was added to a solution of 5-fluoro-2,3-dihydrobenzofuran (2.5g, 18 mmol) in 10 ml acetic anhydride at 10° C. The reaction mixture wasstirred at room temperature for 2 hours then poured into ice-water. Themixture was extracted with methylene chloride (3×60 ml), washed with 1Nsodium hydroxide (5×100 ml) and brine (200 ml). The organic layer wasdried over anhydrous sodium sulfate and filtered. The solvent wasremoved under vacuum to afford a yellow solid: mp 113-114° C.

[0198] Elemental analysis for C₈H₆NO₃ Calc'd: C, 52.47; H, 3.30; N, 7.65Found: C, 52.40; H, 3.21; N, 7.39

INTERMEDIATE 18 5-Fluoro-7-amino-2,3-dihydrobenzofuran

[0199] A mixture of 5-fluoro-7-nitro-2,3-dihydrobenzofuran (2.65 g) and10% palladium on carbon (0.5 g) in ethanol (100 ml) was hydrogenated for3 hours. The catalyst was filtered off and the solvent removed undervacuum. Chromatography (30% ethyl acetate-hexanes) afforded 1.38 g (62%)of product as a white solid: mp 68-70° C.

[0200] Elemental analysis for C₈H₈NO Calc'd: C, 62.74; H, 5.27; N, 9.15Found: C, 62.76; H, 5.32; N, 9.13

INTERMEDIATE 191-Benzyl-4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-piperazine

[0201] A solution of 5-fluoro-7-amino-2,3-dihydrobenzofuran (1.38 g, 9mmol) and bis(2-chloroethyl)-benzylamine (3.14 g, 14 mmol) in butanol(20 ml) was stirred at 100° C. for 10 hours. The salt was filtered off,washed with ethyl ether (30 ml) and dried under vacuum: mp 232-233.5° C.The salt was converted to the free base to afford 2.06 g (73%) of thetitle compound.

[0202] Elemental analysis for C₁₉H₂₁FN₂O.HCl.0.25H₂O Calc'd: C, 64.58;H, 6.42; N, 7.93 Found: C, 64.43; H, 6.27; N, 7.86

INTERMEDIATE 20 4-(5-Fluoro-2,3-dihydro-benzofuran-7-yl)-piperazine

[0203] A mixture of1-benzyl-4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-piperazine (2.06 g,6.6 mmol), 10% palladium on carbon (0.6 g) and ammonium formate (0.83 g,13 mmol) in ethanol (20 ml) was allowed to refux for 2 hours. Thecatalyst was filtered off and the solvent removed under vacuum.Chromatography (10-30% methanol-methylene chloride plus ammoniumhydroxide) afforded 1.10 g (75%) of product as a yellow oil; MS EI m/e222 (M)⁺.

INTERMEDIATE 21 Ethyl 7-nitrobenzofuran-2-carboxylate

[0204] A stirred mixture of 2-hydroxy-3-nitrobenzaldehyde (4.8 g, 59mmol), diethyl bromomalonate (16.8 g, 71 mmol), potassium carbonate(12.1 g, 88 mmol) and N,N′-terephthalylidenebis(4-butylaniline) (1.9 g,5.9 mmol) in toluene (100 ml) was refluxed with a Dean-Stark trap for 24hours. Another 12.1 g potassium carbonate was added to the abovereaction mixtuer, and the resulting mixture was allow to reflux foranother 3 days. The reaction was quenched with water, extracted with(3×200 ml) and washed with 2.0 N sodium hydroxide (100 ml). The organiclayer was dried over anhydrous sodium sulfate and filtered.Chromatography (30% ethyl acetate-hexanes) afforded a yellow solid: mp86.5-87.5° C. (lit¹: mp 88-89° C.).

INTERMEDIATE 22 7-Nitrobenzofuran

[0205] To a suspension of ethyl 7-nitrobenzofuran-2-carboxylate inethanol was added 2 N potassium hydroxide (60 ml). After being heated atreflux for 0.5 hour, the solution was cooled to room temperature andconcentrated to half volume. Concentrated hydrochloric acid was added tothe above mixture and filtered. The solid was washed with water anddired under vacuum with phosphorous pentoxide overnight. The dried solidwas mixed with quinoline (75 ml) and copper oxide (CuO, 0.4 g). Themixture was heated up to 220° C. for 3 hours. The mixture was filteredand the filtrate was concentrated. Chromatography (20% ethylacetate-hexanes) afforded 5.3 g (91%) of product as a yellow solid: mp92-94° C. (lit¹: mp 95.5-97° C.).

INTERMEDIATE 23 7-Aminobenzofuran hydrochloride

[0206] A stirred suspension of 7-nitrobenzofuran (5.3 g, 32 mmol) andRaney nickel (0.1 g) in methanol (70 ml) was heated up to 50° C. Thenhydrazine monohydrate (98%, 4.8 ml, 97 mmol) in methanol (10 ml) wasslowly added to the above solution at temperature 50-60° C. When theaddition was complete, the mixture was allowed to reflux for 2 hours.The Raney nickel was filtered off and the solution was concentrated. Theresidue was dissolved in ethyl acetate and converted to its HCl salt3.68 g (66%) (lit¹: mp 212-213° C.).

INTERMEDIATE 24 1-(7-Benzofuranyl)piperazine

[0207] A solution of 7-aminobenzofuran hydrochloride (3.66 g, 22 mmol)and bis(2-chloroethyl)amine hydrochloride (3.84 g, 22 mmol) inchlorobenzene (80 ml) was heated to reflux for 72 hours. The solvent wasremoved under vacuum, the residue was dissolved in 2.5 N sodiumhydroxide-methylene chloride and extracted with methylene chloride(3×100 ml). The organic layer was dried over anhydrous sodium sulfateand filtered. Chromatography (10-20% methanol-methylene chloride plusammonium hydroxide) afforded 0.66 g (15%) of product as a brown-yellowoil; (lit¹: for HCl salt mp 194.5-195° C.).

INTERMEDIATE 25 4-(5-Fluoro-1H-3-indolyl)-cyclohex-3-enone

[0208] This compound was prepared in the manner described above forintermediate 3c by replacing 4-(5-fluoro-1H-3-indolyl)-cyclohexanoneethylene ketal with 4-(5-fluoro-1H-3-indolyl)-cyclohex-3-enone-ethyleneketal (1.37 g) to afford 1.01 g (88%) of the title compound.

INTERMEDIATE 261-(2-Methoxy-phenyl)-4-(1,4-dioxa-spiro[4,5]dec-8-yl)-piperazine

[0209] A solution of 1,4-cyclohexanedione monoethylene ketal (4.68 g, 30mmol), 1-(2-methoxy-phenyl)piperazine (5.8 g, 30 mmol), sodiumtriacetoxyborohydride (9 g, 42 mmol) and acetic acid (1.8 ml, 30 mmol)in 1,2-dichloroethane (8 ml) was allowed to stir at room temperature for12 hours. The reaction was quenched with 1N sodium hydroxide (pH>9), andextracted with methylene chloride (3×100 ml). The organic layer wasdried over anhydrous sodium sulfate and filtered. Chromatography (10%methanol-ethyl acetate) afforded 9.0 g (90%) of product as a semi-solid.

INTERMEDIATE 27 4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-cyclohexanone

[0210] This compound was prepared in the manner described above forintermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indolewith 1-(2-methoxy-phenyl)-4-(1,4-dioxa-spiro[4,5]dec-8-yl)-piperazine(5.0 g, 15 mmol) to afford 4.0 g (93%) of the title compound.

INTERMEDIATE 28 5-Fluoro-3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]cyclohex-1-enyl}-1H-indole

[0211] This compound was prepared in the manner described above forintermediate 1c by replacing 1,4-cyclohexanedione monoethylene ketalwith 4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexanone (1.44 g, 5mmol). The crude mixture was used in next step without furtherpurification.

INTERMEDIATE 261-(2-Methoxy-phenyl)-4-(1,4-dioxa-spiro[4,5]dec-8-yl)-piperazine

[0212] A solution of 1,4-cyclohexanedione monoethylene ketal (4.68 g, 30mmol), 1-(2-methoxy-phenyl)piperazine (5.8 g, 30 mmol), sodiumtriacetoxyborohydride (9 g, 42 mmol) and acetic acid (1.8 ml, 30 mmol)in 1,2-dichloroethane (8 ml) was allowed to stir at room temperature for12 hours. The reaction was quenched with 1N sodium hydroxide (pH>9), andextracted with methylene chloride (3×100 ml). The organic layer wasdried over anhydrous sodium sulfate and filtered. Chromatography (10%methanol-ethyl acetate) afforded 9.0 g (90%) of product as a semi-solid.

INTERMEDIATE 27 4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-cyclohexanone

[0213] This compound was prepared in the manner described above forintermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indolewith 1-(2-methoxy-phenyl)-4-(1,4-dioxa-spiro[4,5]dec-8-yl)-piperazine(5.0 g, 15 mmol) to afford 4.0 g (93%) of the title compound.

INTERMEDIATE 28 5-Fluoro-3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]cyclohex-1-enyl}-1H-indole

[0214] This compound was prepared in the manner described above forintermediate 1c by replacing 1,4-cyclohexanedione monoethylene ketalwith 4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexanone (1.44 g, 5mmol). The crude mixture was used in next step without furtherpurification.

INTERMEDIATE 29 5-Fluoro-3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]cyclohexyl}-1H-indole

[0215] This compound was prepared in the manner described above forintermediate 2c by replacing 4-(5-fluoro-1H-3-indolyl)-cyclohex-3-en-ethylene ketal with 5-fluoro-3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]cyclohex-1-enyl}-1H-indole (2.0 g) to afford 1.77 g (84%) of product asa mixture of cis and trans isomer.

INTERMEDIATE 30 4-(5-Fluoro-1-methyl-3-indolyl)-cyclohexanone

[0216] To a suspension of sodium hydride (60%, 0.18 g, 4.5 mmol) inanhydrous N, N-dimethylformamide (10 ml) was added4-(5-fluoro-1H-indol-3-yl)-cyclohexanone (0.7 g, 3.0 mmol) at roomtemperature. The mixture was stirred for 0.5 hour, then to the abovesolution was added iodomethane (0.21 ml, 3.3 mmol) at room temperature.The resulting mixture was stirred for another 0.5 hour and quenched withwater. The mixture was extracted with methylene chloride (3×50 ml) andthe organic layer was dried over anhydrous sodium sulfate and filtered.Chromatography (30% ethyl acetate-hexanes) afforded 0.35 g (46%) ofproduct as a yellow oil: MS EI m/e 245 (M⁺).

INTERMEDIATE 31 5-Nitro-quinoxaline

[0217] To a room temperature solution of 3-nitro-o-phenylenediamine (10g, 65.3 mmol) in EtOH (50mL) was added glyoxal (40% in H₂O, 22.47 mL).The reaction mixture was heated at reflux 1 hour, then diluted with H₂O(100 mL). The cooled mixture was extracted with CH₂Cl₂ (2×300 mL) andthe organic layers were combined and washed again with H₂O (500 mL),dried over Na₂SO₄ and concentrated yielding a bright orange solid whichwas recrystallized from EtOAc/Hexanes to give 10.96 (96%) of a tan solidmp 90-92° C.

[0218] Elemental Analysis for C₈H₅N₃O₂ Calc'd C, 54.86; H, 2.88, N;23.99 Found C, 55.12; H, 3.05; N, 24.05.

INTERMEDIATE 32 5-Amino-quinoxaline

[0219] To a three neck 250 mL round bottom flask equipped with a refluxcondenser and nitrogen inlet was added 5-nitro-quinoxaline (4 g, 22.8mmol) dissolved in HOAc (60 mL). The mixture was heated to boiling,removed from heat, and solid Fe powder (3.83 g, 68.6 mmol) was added.Vigorous boiling was observed. The reaction mixture was heated at reflux10 minutes and then poured into H₂O (100 mL) and ice. The aqueoussolution was filtered and basified to pH>10 with 1 M NaOH, and extractedin EtOAc (3×200 mL). The organic layers were combined, dried overNa₂SO₄, and concentrated. The resulting oil was purified by columnchromatography

[0220] (40% EtOAc/Hexanes) yielding 2.03 g (61%) of an orange solid: mp87-90° C.

[0221] Elemental Analysis for C₈H₇N₃ Calc'd C, 66.19; H, 4.86; N, 28.95Found C, 66.25; H, 4.96; N, 29.26

INTERMEDIATE 33 1-Benzyl-4-(quinoxalin-yl)-piperazine

[0222] To a solution of 5-amino-quinoxaline (2.8 g, 19.3 mmol) in BuOH(50 mL) was added bis(2-chloroethyl)-benzlyamine (8.42 g, 38.6 mmol) andEt₃N (5.34 mL, 38.6 mmol). The reaction was stirred at 100° C.overnight. A second portion of Et₃N (5.34 mL, 38.6 mmol) was added andthe reaction stirred at 100° C. an additional 24 hours. The cooledsolution was made alkaline with 2.5 N NaOH (500 mL) and extracted intoEtOAc (3×200 mL). The organic fractions were combined, dried overNa₂SO₄, concentrated and chromatographed (40% EtOAc/Hex) yielding 1.0 g(17%) of a gold oil.

INTERMEDIATE 34 5-(1-Piperazinyl)-quinoxaline

[0223] To a room temperature solution of1-benzyl-4-(quinoxalin-yl)-piperazine (1.0 g, 3.3 mmol) in anhydrousCH₂Cl₂ under nitrogen was added vinyl chloroformate (0.34 mL, 3.9 mmol)drop wise. The reaction mixture was heated at reflux 2 hours. Thereaction was cooled, concentrated to dryness and concentrated HCl (25mL) and 1,4-dioxane (25 mL) were added. The resulting solution wasstirred at ambient temperature overnight. The solution was basified with2.5 N NaOH (300 mL) and extracted into EtOAc (3×200 mL). The organiclayers were combined, dried over Na₂SO₄, concentrated andchromatographed (10% MeOH/CH₂Cl₂/NH₄OH) to give 450 mg (64%) of anorange solid: mp 106-108° C.: MS (+) ESI m/e 215 [M+H]⁺.

INTERMEDIATE 35a 5-(Trifluoromethylsulfonyloxy)-quinoline

[0224] A solution of 5-hydroxy-quinoline (8 g, 55 mmol) and K₂CO₃ (15.2g, 110 mmol) in anhydrous pyridine (60 mL) under nitrogen was cooled to−20° C. Tf₂O (13.97 mL, 83 mmol) was added drop-wise via syringe. Thereaction mixture was stirred 1 hour at −20° C. then warmed to 0° C. for1 hour then stirred at ambient temperature for 48 hours. The reactionmixture was then poured into H₂O (200 mL) and extracted in CH₂Cl₂ (2×200mL). The aqueous layer was acidified with 1 N HCl (100 mL) and backextracted with CH₂Cl₂ (2×200 mL). The organic fractions were dried overNa₂SO₄, concentrated and purified by column chromatography (40%EtOAc/Hexanes) affording 13.97 g (90%) of the product as a pink oil: MSEI m/e 277 (M⁺).

INTERMEDIATE 35b 5-(Trifluoromethylsulfonyloxy)-isoquinoline

[0225] This compound was prepared in the manner described above forIntermediate 35a by replacing 5-hydroxy-quinoline with5-hydroxy-isoquinoline (5 g) to afford 7.71 g (79%) of the titlecompound as a waxy beige solid: MS ESI m/e 278 (M⁺).

INTERMEDIATE 35c 1-(Trifluoromethylsulfonyloxy)-isoquinoline

[0226] This compound was prepared in the manner described forIntermediate 35a by replacing 5-hydroxy-quinoline with isocarbastyril (8g) to afford 9.74 g (64%) of the title compound as a clear oil: MS EIm/e 277 (M⁺).

INTERMEDIATE 36a 1-t-butyl-4-(5-Quinolinyl)piperazine carboxylate

[0227] To an oven-dried 100 mL flask was added Cs₂CO₃ (19.87 g, 61mmol), Pd(OAc)₂ (0.49 g, 2.2 mmol), and BINAP (1.183 g, 1.9 mmol). Thesolids were flushed with N₂ for 10 minutes. A solution of5-(trifluoromethylsulfonyloxy)-quinoline (12 g, 43 mmol) and1-t-butyl-4-piperazine carboxylate (9.67 g, 52 mmol) in THF was thenadded slowly to the reaction flask. The reaction mixture was stirred atroom temperature for 0.5 hour then at 65° C. overnight. The resultingsolution was diluted with ether, filtered through a bed of celite,washed with Et₂O (50 mL) and EtOAc (50 mL). The organic fractions werecombined, dried over Na₂SO₄, filtered, and chromatographed 3 times (10%MeOH/CH₂Cl₂) yielding 1.57 g (12%) of pure product as a beige solid: mp116-118° C.

[0228] Elemental Analysis for C₁₈H₂₃N₃O₂: Calc'd C, 68.98; H, 7.40; N,13.41 Found C, 69.09; H, 7.33; N, 13.08

INTERMEDIATE 36c 1-t-butyl-4-(1-Isoquinolinyl)piperazine carboxylate

[0229] This compound was prepared in the manner described above forIntermediate 36a, replacing 5-(trifluoromethylsulfonyloxy)-quinolinewith 1-(trifluoromethylsulfonyloxy)-isoquinoline (9 g, 32.5 mmol)yielding 2.33 g (25%) of a waxy beige solid: mp 69-71° C.

INTERMEDIATE 37a 5-(1-Piperazinyl)-quinoline

[0230] To a solution of 1-t-butyl-4-(5-quinolinyl)piperazine carboxylate(1.57 g, 5 mmol) in CH₂Cl₂ (2 mL) at 0° C. was added a pre-cooled,premixed, solution of TFA (10 mL), CH₂Cl₂ (20 mL) and MeOH (10 drops).The reaction was warmed slowly to room temperature and allowed to stirovernight. The resulting solution was concentrated, dissolved in H₂O (5mL) and CH₂Cl₂ (5 mL) and made alkaline with NaHCO₃ to pH 9. The aqueousportion was extracted 6×100 mL EtOAc and concentrated yielding 1.0 g(100%) of a yellow oil which solidified upon standing was not purifiedfurther.

INTERMEDIATE 37c 1-(1-piperazinyl)-isoquinoline

[0231] This compound was prepared in the same manner as intermediate 37areplacing 1-t-butyl-4-(5-quinolinyl)piperazine carboxylate with1-t-butyl-4-(1-isoquinolinyl) piperazine carboxylate (2.33 g, 7.4 mmol)affording 1.5 g (95%) of a beige solid: mp 127-130° C.

INTERMEDIATE 38a 6-Methoxy, 8-Amino-quinoline

[0232] To a hot suspension of 6-methoxy, 8-nitro-quinoline in 100 mL ofa mixture of ethanol:acetic acid:water (2:2:1) 3.0 g of iron powder wereadded in portions. The reaction was refluxed for about 2½ hours, themixture was cooled, filtered over celite and basified with sodiumbicarbonate. The product was extracted with ether, dried and the solventwas removed under vaccum to give 3.2 g of the title compound. MS (ES)m/z (relative intensity): 175 (M+H+100).

INTERMEDIATE 38b 8-Amino, 6-Chloro-quinoline

[0233] To a hot suspension of (0.800 g) 6-chloro, 8-nitro-quinoline in25 mL of a mixture of ethanol:acetic acid:water (2:2:1) 0.5 g of ironpowder was added in portions. The reaction was refluxed for about 1½hours, the mixture was cooled, filtered over celite and basified withsodium carbonate. The product was extracted with ether, dried and thesolvent was removed under vaccum to give 0.5 g of the title compound. mp70-73° C. MS (ES) m/z (relative intensity): 179 (M+H+).

[0234] Elemental analysis for C₉H₇Cl N₂ Calculated: C: 60.52; H: 3.95;N: 15.68 Found: C: 60.82; H: 3.77; N: 15.96

INTERMEDIATE 39a 6-Methoxy, 8-piperazino-quinoline

[0235] 6-Methoxy, 8-amino-quinoline (8.2 g) and bis(chloroethyl)aminehydrochloride (9.0 g) were taken in 70 mL chlorobenzene and heated atabout 135° C. with vigorous stirring for 3 days. The reaction never wentto completion. The mixture was cooled. Water was added and extractedwith ether. The aqueous phase was basified with sodium carbonate andextracted with ethyl acetate, dried and the solvent removed. The crudeproduct was filtered through 300 mL of silica gel using 10% MeOH/CH₂Cl₂,20% MeOH/CH₂Cl₂, then 1% NH4OH/80% MeOH/19% CH₂Cl₂, to give 1.5 g of thedesired product. MS (ES) m/z (relative intensity): 244 (M+H+, 100).

INTERMEDIATE 39b 6-Chloro-, 8-piperazino-Quinoline

[0236] 8-amino, 6-chloro-quinoline (0.980 g) and bis(chloroethyl)aminehydrochloride (0.980 g) were taken in 13 mL chlorobenzene and heated atabout 135° C. with vigorous stirring for 5 days. The reaction was cooledtaken in water and extracted with ether. The aquous phase is basifiedwith sodium carbonate and reextracted with ether, dried and the soventwas removed to give 0.400 g of the title compound. MS (ES) m/z (relativeintensity): 248 (M+H+).

INTERMEDIATE 39c 5-Chloro-, 8-piperazino-quinoline

[0237] To a solution of5-chloro,8-(trifluoromethylsulfonyloxy)-quinoline (1.0 g) in 15 mLchlorobenzene excess piperazine (1.0 g) was added. The mixture washeated at 120° C. for 2½ days. The reaction was cooled, poured on waterand the product was extracted with ether, dried over magnesium sulfateto give 0.480 g of product. MS (ES) m/z (relative intensity): 248(M+H+,100).

INTERMEDIATE 39d 5-Fluoro, 8-piperazino-quinoline

[0238] To a solution of5-Fluoro,8-(trifluoromethylsulfonyloxy)-quinoline (1 g) in 5 mLchlorobenzene excess piperazine (2.0 g) were added. The mixture washeated at 120° C. for 2½ days. The reaction was cooled, poured on waterand the product was extracted with ethyl acetate, the organic phase waswashed with dilute NaOH, then with water, dried and the solvent wasremoved. The product was chromatographed on silica gel using 15%methanol/methylene chloride then 79:20:1 methanol:methylenechloride:NH₄OH to give 0.240 g of product. MS (ES) m/z (relativeintensity): 232 (M+H+,100).

INTERMEDIATE 39e 8-piperazino-quinaldine

[0239] To a solution of 8-(trifluoromethylsulfonyloxy)-quinaldine (7 g)in 25 mL chlorobenzene, K₂CO₃ (3.3 g) and excess piperazine (10.0 g)were added. The mixture was heated at 130° C. for 3 days. The reactionwas cooled, poured on water and the product was extracted with ethylacetate, dried over magnesium sulfate. The product was chromatographedon silica gel using 20% methanol/methylene chloride then 79:20:1methanol:methylene chloride:NH₄OH to give 3.2 g of product. MS (ES) m/z(relative intensity): 228 (M+H+,100).

INTERMEDIATE 39f 6-MeO, 4-piperazino-quinoline

[0240] To a solution of 6-MeO, 4-(trifluoromethylsulfonyloxy)-quinoline(2 g) in 10 mL acetonitrile, excess piperazine (2 g) was added. Themixture was heated at about 70° C. for 1½ hours. Water is added and theproduct is extracted with ethyl acetate, dried and the solvent wasremoved to give (2.5 g) of product. MS (ES) m/z (relative intensity):308 (M+H+).

INTERMEDIATE 40a 6-Chloro, 8-Nitro-Quinoline

[0241] A solution of 1.0 g of 6-Chloro-quinoline in 5 ml fuming nitricacid, was heated to almost reflux for 2 days. The reaction was cooled,poured onto ice water and neutralized with concentrated ammoniumhydroxide to about pH 5. The formed precipitate was filtered and driedto give 0.600 g of desired product. mp 149-155° C. MS (ES) m/z (relativeintensity): 209 (M+H+).

INTERMEDIATE 40b 5-Cl-8-(trifluoromethylsulfonyloxy)-quinoline

[0242] To a suspension of 5-Chloro,8-hydroxy-quinoline (8.95 g) in 100mL CH₂Cl₂, TEA is added (20 mL). The suspension dissolved, then cooledto −15° C. A solution of 21.1 g of triflic anhydride in 50 mL of CH₂Cl₂,is added drop by drop with cooling. After complete addition, thereaction was stirred at −15° C. for 1 hour; The reaction was dilutedwith CH₂Cl₂, washed with a solution of NaHCO₃, then with water dried andthe solvent was removed to give 15.0 gr of product. mp 80-83° C. MS (ES)m/z (relative intensity): 312 (M+H+,100). Elemental analysis for C₁₀ H₅ClF₃ NO₃ S Calculated: C : 38.54; H: 1.62; N : 4.49 Found: C: 38.3; H:1.73; N :4.5

INTERMEDIATE 40c 5-Fluoro-8-(trifluoromethylsulfonyloxy)-quinoline

[0243] To a cold solution (−15° C.) of 5-Fluoro,8-hydroxy-quinoline (2.5g) in 20 mL CH₂Cl₂, TEA is added (6.3 mL). To the cold mixture asolution of 6.5 g of triflic anhydride in 10 mL of CH₂Cl₂, is added dropby drop with cooling. After complete addition, the reaction was stirredat 0° C. for 1 hour; The reaction was quenched with water, and theproduct was extracted with ether, dried and the solvent was removed togive 3.4 g of product. MS (ES) m/z (relative intensity): 296 (M+H+,100).

INTERMEDIATE 40d 8-(trifluoromethylsulfonyloxy)-quinaldine

[0244] To a cold solution (−15° C.) of 8-hydroxy-quinaldine (11.5 g) in50 mL CH₂Cl₂, TEA is added (29 mL). To the cold mixture a solution of29.6 g of triflic anhydride in 50 mL of CH₂Cl₂, were added drop by dropwith cooling. After complete addition, the reaction was stirred at −15°C. for 1 hour; The reaction was quenched with water, and the product wasextracted with ether, dried and the solvent was removed to give 20 g ofproduct. MS (ES) m/z (relative intensity): 292 (M+H+).

INTERMEDIATE 41 6-MeO, 4-(trifluoromethylsulfonyloxy)-quinoline

[0245] To a cold solution (−15° C.) of 6-MeO,4-hydroxy-quinoline (5 g)in 30 mL CH₂Cl₂, TEA is added (12 mL). To the cold mixture a solution of12 g of triflic anhydride in 15 mL of CH₂Cl₂, were added drop by dropwith cooling. After complete addition, the reaction was stirred at −15°C. for 1 hour; The reaction was quenched with water, and the product wasextracted with ether, dried and the solvent was removed to give 7 g ofproduct. MS (ES) m/z (relative intensity): 308 (M+H+).

INTERMEDIATE 42a 1-benzyl-4-(6-methoxy-2-methylquinolin-8-yl)piperazine

[0246] A mixture of 8-amino-6-methoxy-2-methylquinoline (1.75 g, 9.30mmol), N-benzyl-bis-dichloroethane (8.9 g, 38.3 mmol), and triethylamine(6.5 mL, 46.6 mmol) in 1-butanol (25 mL) was heated at 100° C. for 20hours. After cooling to room temperature, the reaction was diluted withethyl acetate (50 mL), and poured into saturated aqueous NaHCO₃. Theaqueous layer was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with saturated aqueous NaHCO₃ (50 mL) andbrine (50 mL), then were dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. Excess 1-butanol was azeotroped with hexane(2×500 mL). Flash chromatography on 5.5×18 cm SiO₂ (25% EtOAc/hexane)afforded 1.15 g (36%) of a yellow oil, which crystallized on standing.Recrystallization from hexane provided 0.898 g (28%) of analyticallypure product as yellow crystals: mp 83-85° C.

[0247] Elemental analysis for C₂₂H₂₅N₃O Calc'd: C, 76.05; H, 7.25; N,12.09 Found: C, 75.88; H, 7.37; N, 12.05

INTERMEDIATE 42b 1-benzyl-4-(6-methoxy-3-methylquinolin-8-yl)piperazine

[0248] The title compound was prepared by the same method used for1-benzyl-4-(6-methoxy-2-methylquinolin-8-yl)piperazine, exceptsubstituting 8-amino-6-methoxy-3-methylquinoline (2.82 g, 15.0 mmol) forthe 8-amino-6-methoxy-2-methyl-quinoline. Flash chromatography on 6×20cm SiO₂ (25-30% EtOAc/hexane), with rechromatography of the mixedfractions, provided 1.13 g (22%) of the title compound as a yellow gum.Crystallization from hexane afforded 0.88 g of analytically purecompound as yellow crystals: mp 112-113° C.

[0249] Elemental analysis for C₂₂H₂₅N₃O Calc'd: C, 76.05; H, 7.25; N,12.09 Found: C, 75.83; H, 7.26; N, 12.07

INTERMEDIATE 42c 1-benzyl-4-(6-methoxy-4-methylquinolin-8-yl)piperazine

[0250] A mixture of 8-amino-6-methoxy-4-methylquinoline (3.0 g, 15.9mmol), N-benzyl-bis-dichloroethane (11.1 g, 48.0 mmol), triethyl amine(4.8 g, 48 mmol) and 1-butanol were heated to 100° C. for 24 hours. Thereaction mixture was poured into 2.5 N aqueous NaOH and extracted withethyl acetate (3×200 mL). The combined organic layers were washed withwater (100 mL) and brine (100 mL), then were dried over anhydrous sodiumsulfate, filtered and concentrated to afford 12.0 g of a dark brown oil.Flash chromatography on silica gel (5% methanol/ethyl acetate) provided2.3 g (42%) of the title compound as a thick oil, which solidified uponstanding: mp 154-155° C.

[0251] Elemental analysis for C₂₂H₂₅N₃O Calc'd: C, 76.05; H, 7.25; N,12.09 Found: C, 75.92; H, 7.36; N, 11.96

INTERMEDIATE 43a 4-(6-methoxy-2-methylquinolin-8-yl)piperazine

[0252] A mixture of1-benzyl-4-(6-methoxy-2-methylquinolin-8-yl)piperazine (0.527 g, 1.52mmol), 10% Pd/C (0.20 g), and ammonium formate (0.96 g, 15.2 mmol) inmethanol (10 mL) were heated at reflux under N₂ for 3 hours. TLCanalysis (35% EtOAc/hexane) indicated only a trace of starting materialremained. After cooling to room temperature, the reaction was filteredthrough celite, washing with excess methanol. The filtrate wasconcentrated, diluted with CH₂Cl₂ (50 mL), and washed with saturatedaqueous NaHCO₃. The aqueous layer was extracted with CH₂Cl₂ (2×50 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to afford 0.37 g (95%) of the titlecompound as a yellow oil, which was used in the subsequent reactionwithout purification.

INTERMEDIATE 43b 4-(6-methoxy-3-methylquinolin-8-yl)piperazine

[0253] The title compound was prepared by the same method used for thepreparation of 4-(6-methoxy-2-methylquinolin-8-yl)piperazine, except1-benzyl-4-(6-methoxy-3-methylquinolin-8-yl)piperazine (0.32 g, 0.92mmol) was substituted for the1-benzyl-4-(6-methoxy-2-methylquinolin-8-yl)piperazine. The titlecompound was isolated in nearly quantitative yield and used withpurification in the subsequent reaction.

INTERMEDIATE 43c 4-(6-methoxy-4-methylquinolin-8-yl)piperazine

[0254] A mixture of1-benzyl-4-(6-methoxy-4-methylquinolin-8-yl)piperazine (2.0 g, 5.76mmol), methylene chloride (50 mL) and vinyl chloroformate (0.8 mL, 8.64mmol) were refluxed for 4 hours. The mixture was concentrated, thendissolved in a 1:1 mixture of dioxane/conc. HCl and stirred at ambienttemperature for 18 hours. The reaction mixture was made basic with 2.5 Naqueous NaOH and extracted with ethyl acetate (2×200 mL). The combinedorganic layers were washed with water (100 mL) and brine (100 mL), thenwere dried over anhydrous sodium sulfate, filtered, and concentrated togive 0.6 g (47%) of the title compound: mp 208-209° C.

[0255] Elemental analysis for C₁₅H₁₉N₃O.HCl.0.5 H₂O Calc'd: C, 59.50; H,6.99; N, 13.88 Found: C, 59.44; H, 7.09; N, 13.57

INTERMEDIATE 44a 1-benzyl-4-(6-methoxy-5-methylquinolin-8-yl)piperazine

[0256] This compound was prepared in a manner similar to that used for1-benzyl-4-(6-methoxy-4-methylquinolin-8-yl)piperazine to give 3.0 g(56%) of pure title compound: mp 129-133° C.

[0257] Elemental analysis for C₂₂H₂₅N₃O Calc'd: C, 76.05; H, 7.25; N,12.09 Found: C, 75.61; H, 7.35; N, 11.97

INTERMEDIATE 44b 1-benzyl-4-(6-methoxy-5-chloro-quinolin-8-yl)piperazine

[0258] This compound was prepared in a manner similar to that used for1-benzyl-4-(6-methoxy-4-methylquinolin-8-yl)piperazine to give 1.9 g(35%) of pure title compound: mp 138-140° C.

[0259] Elemental analysis for C₂₁H₂₂ClN₃O Calc'd: C, 68.56; H, 6.03; N,11.42 Found: C, 68.26; H, 5.98; N, 11.45

INTERMEDIATE 45a 4-(6-methoxy-5-methylquinoline-8-yl)piperazine

[0260] A mixture of methanol (1 mL), 10% Pd/C (0.12 g),1-benzyl-4-(6-methoxy-5-methylquinolin-8-yl)piperazine (0.8 g, 2.3mmol), and ammonium formate (0.88 g, 13.9 mmol) were refluxed for 45minutes. The reaction mixture was filtered through celite andconcentrated. The residue was diluted with 1 N aqueous NaOH (50 mL) andextracted with ethyl acetate (3×75 mL). The combined organic layers werewashed with water (50 mL) and brine(50 mL), then were dried overanhydrous Na₂SO₄, filtered, and concentrated to give 0.52 g (61%) of thetitle compound as a thick oil. MS (ES) m/z: 258 (M+H+).

INTERMEDIATE 45b 4-(6-methoxy-5-chloro-quinolin-8-yl)piperazine

[0261] This compound was prepared in a manner as similar to that used4-(6-methoxy-5-methylquinoline-8-yl)piperazine to give 0.48 g (68%) ofpure title compound as a thick oil. MS (ES) m/z: 278 (M+H+).

INTERMEDIATE 46 5-Bromo-6-methoxy-quinoline

[0262] To a solution of 6-methoxyquinoline (5 g, 31.4 mmol) in aceticacid (50 mL) was slowly added Br₂ neat (1.62 mL, 31.4 mmol). Thereaction mixture was stirred at ambient temperature for 1 hour and thenpoured onto ice. Saturated aqueous sodium bisulfite was added, and theresulting slurry was extracted into EtOAc (2×200 mL). The organicfractions were combined, dried over Na₂SO₄, concentrated, and purifiedby column chromatography (5% MeOH/CH₂Cl₂) affording 4.39 g of the titlecompound as the acetate salt. The free base was prepared by washing thesalt with 1 N NaOH (50 mL) and H₂O (100 mL) and extracting into CH₂Cl₂(200 mL). The organic fractions were concentrated affording 3.89 g (52%)of the title compound as a pink solid.

[0263] Elemental analysis for C₁₀H₈BrNO Calc'd: C, 50.45; H, 3.39; N,5.88 Found: C, 50.34; H, 3.25; N, 6.09

INTERMEDIATE 47 4-Bromo-2-nitrophenylamine

[0264] To a solution of 2-nitro-phenylamine (13.8 g, 100 mmol) in HOAc(150 mL) was added NBS (18 g, 101 mmol). The reaction mixture wasstirred and heated to reflux over 1 hour. The cooled reaction mixturewas poured into H₂O (1000 mL) and stirred for 15 minutes. The resultingorange slurry was filtered and washed with H₂O (300 mL) affording a20.26 g (93%) of the title compound as a bright orange solid.

[0265] Elemental analysis for C₆H₅BrN₂O₂ Calc'd: C, 33.21; H, 2.32; N,12.91 Found: C, 33.15; H, 2.31; N, 12.75

[0266] Ref: Montash Chem EN 1994, 125 p. 723-730

INTERMEDIATE 48 6-Bromo-8-nitro-quinoline

[0267] A sulfuric acid solution was prepared by adding H₂SO₄ (50 mL) toan 250 mL flask containing H₂O (20 mL) cooled in an ice bath. To thissolution was added glycerol (12 mL, 16.5 mmol), m-nitrobenzene sulfonicacid sodium salt (11.4 g, 5.06 mmol), and 4-bromo-2-nitrophenylamine (10g, 4.6 mmol). The reaction mixture was heated at 135° C. for 3 hours.The warm reaction mixture was poured into ice H₂O (200 mL) and extractedinto 50% MeOH/EtOAc (2×200 mL), dried over Na₂SO₄ and concentrated. Theresulting brown solid was triturated with EtOH and filtered affording3.8 g (33%) of a pink solid: mp 172-174° C.

[0268] Elemental analysis for C₉H₅BrN₂O₂ Calc'd: C, 42.72; H, 1.99; N,11.07 Found: C, 42.69; H, 1.85; N, 11.01

[0269] Ref: Mantash Chem EN 1994, 125 p. 723-730

INTERMEDIATE 49 6-Bromo-8-amino-quinoline

[0270] To a solution of 6-bromo-8-nitro-quinoline (4 g, 1.58 mmol) inEtOH/HOAc/H₂O (50 mL/50 mL/25 mL) was added iron metal (3.18 g, 5.69mmol). The resulting solution was heated at reflux for 3 hours. Thecooled reaction mixture was neutralized with 2.5 N NaOH, filteredthrough celite to remove iron solids and washed with EtOAc. The eluentwas extracted into EtOAc (3×200 mL), combined, dried over Na₂SO₄ andconcentrated. The resulting oil was purified by column chromatography(40% EtOAc/hexanes) affording 3.19 g (91%) of a yellow solid: mp142-145° C.

[0271] Elemental analysis for C₉H₇BrN₂ Calc'd: C, 48.46; H, 3.16; N,12.56 Found: C, 48.04; H, 2.93; N, 12.36

INTERMEDIATE 50 8-(4-benzyl-piperazin-1-yl)-6-bromo-quinoline

[0272] The free base of bis(2-chloroethyl)-benzlyamine (5.12 g, 19.3mmol) was prepared by washing the HCl salt with 1 M NaOH (200 mL) andextracting into EtOAc. The resulting organic phases were dried overNa₂SO₄ and concentrated. To this flask was added6-bromo-8-amino-quinoline (2.15 g, 9.6 mmol), n-BuOH (100 mL), and Et₃N(4 mL, 28.9 mmol). The resulting reaction mixture was stirred at 100° C.overnight. TLC analysis showed starting amine was still present,therefore an additional portion of bis(2-chloroethyl)-benzylaminehydrochloride (5 g) was added. The reaction was heated an additional 72hours. The cooled reaction mixture was quenched with 1 M NaOH (200 mL)and extracted into EtOAc (3×200 mL). The organic fractions werecombined, dried over Na₂SO₄, and concentrated. The resulting gold oilwas purified three times by column chromatography (40% EtOAc/hexanes)affording 1.2 g (33%) of a viscous orange oil which solidified uponstanding: mp 65-68° C., MS (+) APCI m/z 382 [M+H]⁺.

[0273] Elemental analysis for C₂₀H₂₀BrN₃.0.75H₂O Calc'd: C, 60.69; H,5.48; N, 10.62 Found: C, 60.81; H, 5.02; N, 10.88

INTERMEDIATE 51 6-Bromo-8-piperazin-1-yl-quinoline

[0274] To a solution of 8-(4-benzyl-piperazin-1-yl)-6-bromo-quinoline(1.6 g, 4.2 mmol) in dichloroethane (50 mL) under a N₂ atmosphere wasadded chloroethylchloroformate (1.26 mL, 12.6 mmol) and the reactionmixture was heated at 80° C. for 4 hours, and at ambient temperaureovernight. No reaction was observed by TLC, therefore vinylchloroformate (0.35 mL, 6.3 mmol) was added and the reaction was heatedat 80° C. for another 4 hours. The cooled reaction was poured into H₂Oand extracted into CH₂Cl₂ (2×100 mL) and EtOAc (100 mL). The organicfractions were combined, dried over Na₂SO₄, and left in EtOAc overnight.The organic layer was concentrated and purified by column chromatography(10%MeOH/CH₂Cl₂+NH₄OH) affording 1.03 g (84%) of a brown foam. MS (+)APCI m/z 292 [M+H]⁺.

INTERMEDIATE 52 6-hydroxy-8-nitro-quinoline

[0275] A solution of 6-methoxy-8-nitro-quinoline (9 g, 44.1 mmol) in HBr(100 mL) was heated at 110° C. overnight. Additional HBr (80 mL) wasadded and the reaction continued to heat for an additional 24 hours. Thecooled reaction mixture was basified with 2.5 N NaOH (800 mL) andextracted into EtOAc (2×300 mL). The organic fractions were combined,dried over Na₂SO₄ and purified by column chromatography (50%EtOAc/hexane) to afford 2.71 g (32%) of the title compound as a whitesolid: mp discolors above 100° C., MS (−) ESI m/z 189 [M−H]⁻.

INTERMEDIATE 53 6-Ethoxy-8-nitro-quinoline

[0276] A solution of 6-hydroxy-8-nitro-quinoline (2.5 g, 13.2 mmol),ethylbromide (1.08 mL, 14.5 mmol), and K₂CO₃ (4 g, 26.4 mmol) in DMF (50mL) under a nitrogen atmosphere was heated at 40° C. for 5 hours. Thecooled reaction mixture was poured into H₂O (200 mL) and extracted intoEtOAc (2×200 mL). The organic fractions were combined, dried over Na₂SO₄and concentrated. The resulting beige solid was triturated with 40%EtOAc/hexane to give 2.46 g (85%) of the title compound as beigecrystals.

[0277] Elemental analysis for C₁₁H₁₀N₂O₃ Calc'd: C, 60.55; H, 4.62; N,12.84 Found: C, 60.15; H, 4.50; N, 12.75

INTERMEDIATE 548-(4-benzyl-piperazin-1-yl)-6-methoxy-1,2,3,4-tetrahydroquinoline

[0278] A solution of 8-(4-benzyl-piperazin-1-yl)-6-methoxy-quinoline (1g, 3 mmol) in HOAc (100 mL) was hydrogenated over PtO₂ (300 mg) at 40psi overnight. The reaction mixture was filtered through a pad of celiteand was washed with EtOAc (50 mL). The filtrate was concentrated. Theresulting gold oil was purified by column chromatography(10%MeOH/CH₂Cl₂+NH₄OH) affording 330 mg (45%) of a viscous gold oil. Ananalytical sample was prepared as the HCl salt from EtOAc. MS EI m/z 247M⁺.

[0279] Ref: J. Chem Soc Perkins I 1980 p. 1933-1939

INTERMEDIATE 55 [1,6]naphthyridine

[0280] A sulfuric acid solution was prepared by adding H₂SO₄ (100 mL) toH₂O (57 mL) cooled in an ice bath. To this solution was added glycerol(33 mL, 457 mmol), m-nitrobenzene sulfonic acid sodium salt (48 g, 212mmol) and 4-amino-pyridine (10 g, 106 mmol). The reaction mixture washeated at 135° C. for 4 hours. The cooled reaction mixture wasbasicified with 2.5 N NaOH (500 mL) with cooling in an ice bath, andextracted into CH₂Cl₂ (3×200 mL). The organic fractions were combined,dried over Na₂SO₄ and concentrated. The resulting oil was purified bycolumn chromatography (5% MeOH/CH₂Cl₂) affording 5.04 g (36%) as a darkorange oil. An analytical sample was prepared as the HCl salt from EtOAcyielding an orange low melting solid. MS EI m/z 130 M⁺.

[0281] Ref: Chem Pharm Bull. 1971, 19, 9, p. 1751-1755

INTERMEDIATE 56 8-Bromo-[1,6]-naphthyridine

[0282] To a stirred solution of [1,6]-naphthyridine (4.73 g, 36.4 mmol)in CCl₄ (200 mL) was added Br₂ (2.25 mL, 43.7 mmol) in CCl₄ (35 mL)dropwise via an addition funnel. The resulting solution was heated atreflux for 1 hour. Pyridine (2.94 mL, 36.4 mmol) in CCl₄ (30 mL) wasadded dropwise to the refluxing solution, and the mixture was refluxedovernight. The cooled reaction mixture was filtered, and the solids weredigested with 1 M NaOH (200 mL) for 1 hour. The basic solution wasextracted into CH₂Cl₂ (2×200 mL), and the organic fractions werecombined, dried over Na₂SO₄ and concentrated. The resulting oil waspurified by column chromatography (10% EtOAc/CH₄Cl₂) affording 2.03 g(27%) of the title compound as yellow crystals: mp 79-81° C.

[0283] Elemental analysis for C₈H₅BrN₂ Calc'd: C, 45.97; H, 2.41; N,13.40 Found: C, 45.72; H, 2.34; N, 13.36

[0284] Ref: JOC 1968, 33, 4, p. 1384-1387

INTERMEDIATE 57 8-piperazin-1-yl-[1,6]-naphthyridine

[0285] To an oven-dried 100 mL flask under a nitrogen atmosphere wasadded 8-bromo-[1,6]-naphthyridine (1.3 g, 6.2 mmol), piperazine (3.21 g,37.3 mmol), and sodium t-butoxide (900 mg, 9.33 mmol). The solids weresuspended in anhydrous o-xylenes (40 mL), and Pd(dba) (285 mg, 5 mol %)and P(t-Bu)₃ (0.31 mL, 1.24 mmol) were added. The reaction mixture washeated at 120° C. for 3 hours. The cooled reaction mixture was pouredinto H₂O (100 mL) and extracted into EtOAc (1×100 mL) and CH₂Cl₂ (2×100mL). The organic fractions were combined, dried over Na₂SO₄,concentrated, and the resulting oil was chromatographed (10%MeOH/CH₂Cl₂+NH₄OH) affording 470 mg (35%) of the title compound as adark gold oil. An analytical sample was prepared as the HCl salt fromEtOAc giving a brown solid: mp decomposes above 200° C. MS (+) APCI m/z215 [M+H]⁺.

[0286] Ref: Tet. Lett. 1998, 39, p. 617-620

INTERMEDIATE 58 4-(6-Methylamino-quinolin-8-yl)-piperazine-1-carboxylicacid ethyl ester

[0287] To an oven-dried 25 mL round bottom flask was added Cs₂CO₃ (1.55g, 4.76 mmol), BINAP (300 mg, 3 mol %), Pd(OAc)₂ (100 mg, 3 mol %) andkept under vacuum overnight. To this reaction vessel under a nitrogenatmosphere was added 8-(4-benzyl-piperazin-1-yl)-6-bromo-quinoline (1.3g, 3.4 mmol), anhydrous toluene (12 mL) and benzylmethylamine (0.53 mL,4.1 mmol). The reaction mixture was heated at 100° C. overnight. Thecooled reaction mixture was diluted with Et₂O (15 mL), filtered toremove solids, washed with EtOAc (10 mL) and concentrated. The resultingoil was purified by column chromatography (40% EtOAc/hexane) affording830 mg (59%) ofbenzyl-[8-(4-benzyl-piperazin-1-yl)-quinolin-6-yl]-methyamine as anorange foam.

[0288] To a solution ofbenzyl-[8-(4-benzyl-piperazin-1-yl)-quinolin-6-yl]-methyamine (800 mg,1.89 mmol) in anhydrous CH₂Cl₂ (100 mL) was added vinyl chloroformate(0.48 mL, 5.68 mmol) and heated at reflux overnight. A second aliquot ofvinyl chloroformate (0.48 mL) was added and the reaction refluxed anadditional 24 hours. The cooled reaction mixture was diluted with H₂O(50 mL) and extracted into CH₂Cl₂ (2×50 mL). The combined organic phaseswere dried over Na₂SO₄, filtered and concentrated. The resulting oil waspurified by column chromatography (40% EtOAc/hexane) affording 600 mg ofa monodebenzylated product. This material was dissolved in EtOH (100 mL)and 10% Pd/C (150 mg) and ammonium formate (244 mg, 4.5 mmol) wereadded. The reaction was heated at reflux overnight. Additional ammoniumformate (250 mg) was added and the reaction refluxed for an additional72 hours. The cooled reaction mixture was filtered through a pad ofcelite and washed with EtOAc (200 mL), concentrated and purified bycolumn chromatography (10% MeOH/CH₂Cl₂) affording 400 mg of the titlecompound as a dark gold oil. An analytical sample was prepared as theHCl salt from EtOAc as an orange solid: mp decomposes above 85° C. MS(+) APCI m/z 315 [M+H].

INTERMEDIATE 59 4-methoxy-2,6-dinitro-phenylamine

[0289] To a stirred solution of HNO₃ (65 mL) was added4-methoxy-2-nitro-phenylamine (15 g, 89.3 mmol). The reaction mixturewas stirred at room temperature overnight. The dark red precipitate wasfiltered and washed with H₂O (400 mL) affording 10.01 g (53%) of thetitle compound.

INTERMEDIATE 60 7-Methoxy-quinoxalin-5-ylamine

[0290] A solution of 4-methoxy-2,6-dinitro-phenylamine (5 g, 23.5 mmol)in EtOH (200 mL) was hydrogenated over 10% Pd/C (2 g) at 40 psi for 1hour. After H₂ uptake had ceased, the reaction was filtered through apad of celite and washed with EtOAc (50 mL) and concentrated. Glyoxal (8ml, 704 mmol) and EtOH (50 mL) were immediately added and the reactionwas heated at reflux for 2 hours. The cooled reaction was diluted withH₂O (50 mL) and extracted into CH₂Cl₂ (3×100 mL). The organic phaseswere combined, dried over Na₂SO₄, filtered and concentrated. Theresulting oil was purified by column chromatography (10% MeOH/CH₂Cl₂)affording 430 mg (10%) as a red oil. An analytical sample was preparedas the HCl salt from EtOAc affording a red solid.

INTERMEDIATE 61 (1-Oxy-pyridin-3-yl)-acetonitrile

[0291] A solution of 3-pyridylacetonitrile (11 g, 93.1 mmol), HOAc (55mL), and 30% H₂O₂ (17 mL) was heated at 95° C. overnight, and at roomtemperature for 72 hours. H₂O (50 mL) was added to the reaction mixtureand the resulting solution was concentrated. This was repeated withadditional H₂O (100 mL). Toluene (2×100 mL) was used to remove residualH₂O, and the resulting white solid was dried under vacuum overnightaffording a waxy white solid: mp 120-125° C.; MS (+) APCI m/z 135[M+H]⁺.

[0292] Ref: JACS 1959, 81 p. 740-743

INTERMEDIATE 62 3-Cyanomethyl-pyridine-2-carbonitrile

[0293] To a suspension of (1-oxy-pyridin-3-yl)-acetonitrile (10 g, 75mmol) in anhydrous CH₂Cl₂ under a nitrogen atmosphere was addedtrimethylsilylcyanide (10.95 mL, 82 mmol) and dimethylcarbamoylchloride(7.55 mL, 82 mmol). The reaction mixture was stirred at room temperaturefor 72 hours and then concentrated. EtOAc (100 mL) was added to theresidue and the organic phase was washed with 1 M NaOH (150 mL), driedover Na₂SO₄, filtered and concentrated. The resulting solid was purifiedby column chromatography (50% EtOAc/hexanes) affording 7.08 g (66%) of ayellow solid: mp 48-51° C.; MS (+) APCI m/z 144 [M+H]⁺.

[0294] Ref: WO 9818796

INTERMEDIATE 63 6-Methoxy-[1,7]naphthyridin-8-ylamine

[0295] To an oven-dried 250 mL flask under a nitrogen atmosphere wasadded anhydrous MeOH (200 mL). Na metal (1.07 g, 44 mmol) was weighed toa small beaker containing hexane and then transferred to the reactionvessel. After dissolution of the sodium,3-cyanomethyl-pyridine-2-carbonitrile (5.3 g, 37 mmol) dissolved inanhydrous MeOH (10 mL) was added to the reaction. The resulting solutionwas heated at 80° C. for 3 hours, then stirred at room temperatureovernight. The reaction mixture was concentrated to remove MeOH andextracted into CH₂Cl₂ (2×200 mL). The organic phases were combined,dried over Na₂SO₄, filtered, concentrated and unsuccessfullychromatographed (2% MeOH/CH₂Cl₂). The mixed fractions were combined andrecrystalized from EtOAc/hexane affording 1.16 g (18%) of the titlecompound as a yellow solid. The mother liquor was re-chromatographed(50% EtOAc/hexanes) to afford an additional 560 mg (9%) of product: mpdecomposes above 110° C.; MS (+) APCI m/z 176 [M+H]⁺.

[0296] Ref: Tet. Lett. 1975 p. 173-174

INTERMEDIATE 64 6-Methoxy-8-piperazin-1-yl-[1,7]naphthyridine

[0297] A solution of 6-methoxy-[1,7]naphthyridin-8-ylamine (2.25 g, 12.8mmol), bis(2-chloroethyl)-benzlyamine (10.25 g, 38.6 mmol) and Et₃N(5.34 mL, 38.6 mmol) in BuOH (100 mL) was heated at 100° C. for 72hours. The cooled reaction mixture was poured into H₂O (100 mL) and 2.5N NaOH (100 mL), and extracted into EtOAc (2×200 mL). The organic phaseswere combined, dried over Na₂SO₄, filtered and concentrated. Theresulting oil was purified twice by column chromatography (10%MeOH/CH₄Cl₂) affording a dark gold oil with BuOH impurity. This oil wasdissolved in EtOH (50 mL) and 10% Pd/C (390 mg) and ammonium formate(730 mg) was added. The reaction mixture was heated at 80° C. for 2.5hours. The cooled reaction mixture was filtered through a pad of celiteand washed with EtOAc (50 mL). The organic phase was concentrated andpurified by column chromatography (10% MeOH/CH₂Cl₂+NH₄OH) affording 270mg of the title compound as a dark orange oil. An analytical sample wasprepared as the HCl salt from EtOAc.

INTERMEDIATE 65 4-Piperazin-1-yl-1,3-dihydro-benzoimidazol-2-one

[0298] To a solution of4-(4-benzylpiperazin-1-yl)-1,3-dihydro-benzoimidazol-2-one (1 g, 3.2mmol) in anhydrous CH₂Cl₂ (50 mL) was added vinyl chloroformate (0.41mL, 4.87 mmol) under a nitrogen atmosphere. The reaction mixture washeated at reflux for 2 hours, and then a second aliquot of vinylchloroformate (0.41 mL) was added. The reaction was refluxed anadditional 3 hours. The cooled reaction mixture was concentrated, anddioxan (25 mL) and conc. HCl (25 mL) were added to the residue. Theresulting solution was stirred at room temperature for 72 hours. Thereaction was basicified with 2.5 N NaOH (300 mL) and extracted inMeOH/EtOAc (2×200 mL). The organic fractions were combined, dried overNa₂SO₄ and concentrated and the resulting oil purified by columnchromatography affording 393 mg (46%) as the oxalate salt. MS (+) ESIm/z 219 [M+H]⁺.

INTERMEDIATE 66 6-Methoxy-1H-indol-4-ylamine

[0299] To a solution of 5-methoxy-2-methyl-1,3-dinitrobenzene¹ (3.28 g,15 mmol) in 15 mL dry N,N-dimethylformamide was addedN,N-dimethyformamide dimethyl acetal (6.16 mL, 45 mmol) and pyrrolidine(1.3 mL, 15 mmol). The reaction mixture was heated at 120° C. until TLCanalysis showed complete consumption of the5-methoxy-2-methyl-1,3-dinitrobenzene. N,N-Dimethylformamide was removedunder the vacuum, affording a dark red material, which was dissolved indry benzene and hydrogenated at 50 psi with 10% Pd/C (0.1 g) for 4hours. The catalyst was filtered off and the solvent removed undervacuum. Chromatography (25% ethyl acetate/hexane) afforded 1.0 g (40%)of the desired product as a yellow solid: mp 83-86° C.; MS EI m/e 162.

INTERMEDIATE 67 4-(4-Benzyl-piperazin-1-yl)-6-methoxy-1H-indole

[0300] A solution of 6-methoxy-1H-indol-4-ylamine (0.76 g, 4.7 mmol) andbis(2-chloroethyl)-benzylamine (2.72 g, 11.7 mmol) in 1-butanol (20 mL)was stirred at 100° C. for 18 hours then poured into aqueous sodiumcarbonate solution. The mixture was extracted with ethyl acetate (3×60mL). The organic layer was dried over anhydrous sodium sulfate andfiltered. The solvent was removed under vacuum. Chromatography (30%ethyl acetate/hexane) afforded 0.60 (40%) of product as a gray oil. MS(+) APCI (M+H)⁺m/e 322.

INTERMEDIATE 68 6-Methoxy-4-piperazin-1-yl-1H-indole

[0301] A mixture of 4-(4-benzyl-piperazin-1-yl)-6-methoxy-1H-indole(0.37 g, 1.1 mmol), 10% Pd/C (0.05 g) and ammonium formate (0.15 g, 2.2mmol) in ethanol (20 mL) was allowed to reflux for 2 hours. The catalystwas filtered off and the solvent removed under vacuum. Chromatography(10% methanol/methylene chloride plus ammonium hydroxide) afforded 0.2 g(75%) of product as a yellow foam. MS (EI) m/e 231.

EXAMPLE 1a3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0302] A solution of 4-(1H-indol-3-yl)-cyclohexanone (0.53 g,2.5 mmol),1-(indol-4-yl)piperazine (0.5g, 2.5 mmol), sodium triacetoxyborohydride(0.78 g, 3.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in1,2-dichloroethane (11 ml) was allowed to stir at room temperatureovernight. The reaction was quenched with 1N sodium hydroxide (10 ml),extracted with methylene chloride (3×60 ml), and washed with brine (3×60ml). The organic layer was dried over anhydrous sodium sulfate andfiltered. Chromatography (10% methanol-ethyl acetate) afforded 0.52 g(53%) of product as a white solid: mp 85-87° C.

[0303] The HCl salt was prepared in ethyl acetate: mp 198-200° C.Elemental analysis for C₂₆H₃₀N₄.HCl Calc'd: C, 68.25; H, 7.38; N, 12.25Found: C, 68.12; H, 7.16; N, 11.93

EXAMPLE 1b 3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0304] The trans compound was isolated at the same time as the cisisomer in 21% yield (0.21 g) as a white solid: mp 105-107° C.

[0305] The HCl salt was prepared in ethyl acetate: mp 305° C.(decomposed). Elemental analysis for C₂₆H₃₀N₄.HCl Calc'd: C, 68.25; H,7.38; N, 12.25 Found: C, 68.12; H, 7.16; N, 11.93

EXAMPLE 2a 4-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0306] A solution of 4-(4-fluoro-1H-indol-3-yl)-cyclohexanone (0.88 g,3.8 mmol), 1-(indol-4-yl)piperazine (0.7 g, 3.5 mmol), sodiumtriacetoxyborohydride (1.1 g, 5.2 mmol) and acetic acid (0.4 ml, 7 mmol)in 1,2-dichloroethane (20 ml) was allowed to stir at room temperatureovernight. The reaction was quenched with 1N sodium hydroxide (10 ml),extracted with methylene chloride (3×60 ml), and washed with brine (3×60ml). The organic layer was dried over anhydrous sodium sulfate andfiltered. Chromatography (5-7% methanol-ethyl acetate) afforded 1.14 g(79%) of product as a white foam.

[0307] The HCl salt was prepared in ethanol: mp 283-285° C. Elementalanalysis for C₂₆H₂₉FN₄.HCl.0.25H₂O Calc'd: C, 68.26; H, 6.72; N, 12.25Found: C, 68.16; H, 6.74;N, 12.04

EXAMPLE 2b 4-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0308] The trans compound was isolated at the same time as the cisisomer in 17% yield (0.24 g) as a white solid: mp 206-208° C.

[0309] The HCl salt was prepared in ethanol: mp 297-299° C. Elementalanalysis for C₂₆H₂₉FN₄.HCl.H₂O Calc'd: C, 66.30; H, 6.85; N, 11.90Found: C, 66.17; H, 6.51; N, 11.70

EXAMPLE 3a 5-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0310] This compound was prepared in the manner described above forExample 2 by replacing 4-(4-fluoro-1H-indol-3-yl)-cyclohexanone with4-(5-fluoro-1H-indol-3-yl)-cyclohexanone (0.56 g, 2.5 mmol) to afford0.54 g (52%) of product as a white solid: mp 108-110° C.

[0311] The HCl salt was prepared in ethyl acetate: mp 215-217° C.Elemental analysis for C₂₆H₂₉FN₄.HCl.0.36C₄H₈O₂ Calc'd: C, 67.37; H,6.88; N, 11.45 Found: C, 67.18; H, 6.72; N, 11.18

EXAMPLE 3b 5-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0312] The trans compound was isolated at the same time as the cisisomer in 30% yield (0.31 g) as a white solid: mp 112-114° C.

[0313] The HCl salt was prepared in ethanol: mp 280° C. (decomposed).Elemental analysis for C₂₆H₂₉FN₄.HCl Calc'd: C, 66.81; H, 6.81; N, 11.99Found: C, 66.44; H, 6.66; N, 11.74

EXAMPLE 4a 6-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0314] This compound prepared in the manner described above for Example2 by replacing was 4-(4-fluoro-1H-indol-3-yl)-cyclohexanone with4-(6-fluoro-1H-indol-3-yl)-cyclohexanone (1.15 g, 5.0 mmol) to afford1.06 g (51%) of product as a white foam.

[0315] The HCl salt was prepared in ethanol: mp 250-252° C.(decomposed). Elemental analysis for C₂₆H₂₉FN₄.HCl Calc'd: C, 67.37; H,6.88; N, 11.45 Found: C, 67.18; H, 6.72; N, 11.18

EXAMPLE 4b 6-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0316] The trans compound was isolated at the same time as the cisisomer in 27% yield (0.55 g) as a white foam.

[0317] The HCl salt was prepared in ethanol: mp 319-320° C.(decomposed). Elemental analysis for C₂₆H₂₉FN₄.HCl Calc'd: C, 66.81; H,6.81; N, 11.99 Found: C, 66.44; H, 6.66; N, 11.74

EXAMPLE 5a 5-Bromo-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0318] This compound was prepared in the manner described above forExample 2 by replacing 4-(4-fluoro-1H-indol-3-yl)-cyclohexanone with4-(5-bromo-1H-indol-3-yl)-cyclohexanone (0.75 g, 2.5 mmol) to afford0.81 g (68%) of product.

[0319] The HCl salt was prepared in ethyl acetate: mp 276° C. Elementalanalysis for C₂₆H₂₉BrN₄.HCl Calc'd: C, 60.23; H, 5.93; N, 10.81 Found:C, 59.95; H, 5.83; N, 10.64

EXAMPLE 5b 5-Bromo-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0320] The trans compound was isolated at the same time as the cisisomer in 24% yield (0.29 g).

[0321] The HCl salt was prepared in ethyl acetate: mp>300° C. Elementalanalysis for C₂₆H₂₉BrN₄.HCl Calc'd: C, 60.75; H, 5.88; N, 10.90 Found:C, 60.38; H, 5.89; N, 10.61

EXAMPLE 6a 5-Chloro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0322] A solution of 4-(5-chloro-1H-indol-3-yl)-cyclohexanone (0.78 g,3.1 mmol), 1-(indol-4-yl)piperazine (0.6 g, 3 mmol), sodiumtriacetoxyborohydride (0.95 g, 4.5 mmol) and acetic acid (0.34 ml, 6mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at roomtemperature overnight. The reaction was quenched with 1N sodiumhydroxide (10 ml), extracted with methylene chloride (3×60 ml) andwashed with brine (3×60 ml). The organic layer was dried over anhydroussodium sulfate and filtered. Chromatography (5% methanol-ethyl acetate)afforded 0.84 g (65%) of product as a white foam.

[0323] The HCl salt was prepared in ethanol: mp 283-285° C. Elementalanalysis for C₂₆H₂₉ClN₄.HCl.0.25H₂O Calc'd: C, 65.46; H, 6.69; N, 11.45Found: C, 65.14; H, 6.73; N, 11.33

EXAMPLE 6b 5-Chloro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0324] The trans compound was isolated at the same time as the cisisomer in 24% yield (0.32 g) as a white foam.

[0325] The HCl salt was prepared in ethanol: mp 314-315.5° C. Elementalanalysis for C₂₆H₂₉ClN₄.HCl.0.25H₂O Calc'd: C, 65.65; H, 6.60; N, 11.62Found: C, 65.50; H, 6.50; N, 11.30

EXAMPLE 7a3-{4-[(1,4-cis)-4-(1H-indol-4-yl)-piperazinyl-1-yl]cyclohexyl}-1H-indole-5-carbonitrile

[0326] This compound was prepared in the manner described above forExample 2 by replacing 4-(4-fluoro-1H-indol-3-yl)-cyclohexanone with4-(5-cyano-1H-indol-3-yl)-cyclohexanone (0.71 g, 3.0 mmol) to afford0.38 g (30%) of product.

[0327] The HCl salt was prepared in ethyl acetate: mp 216-218° C.Elemental analysis for C₂₇H₂₉N₅.HCl.0.33C₄H₈SO₂ Calc'd: C, 66.25; H,6.94; N, 13.64 Found: C, 66.05; H, 6.54; N, 13.28

EXAMPLE 7b3-{4-[(1,4-trans)-4-(1H-indol-4-yl)-piperazinyl-1-yl]cyclohexyl}-1H-indole-5-carbonitrile

[0328] The trans compound was isolated at the same time as the cisisomer in 25% yield (0.32 g).

[0329] The HCl salt was prepared in ethyl acetate: mp>310° C. Elementalanalysis for C₂₇H₂₉N₅.HCl Calc'd: C, 68.48; H, 6.71; N, 14.79 Found: C,68.43; H, 6.54; N, 14.63

EXAMPLE 8a 5-Methoxy-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0330] A solution of 4-(5-methoxy-1H-indol-3-yl)-cyclohexanone (1.2 g, 5mmol), 1-(indol-4-yl)piperazine (1 g, 5 mmol), sodiumtriacetoxyborohydride (1.47 g, 6.2 mmol) and acetic acid (0.28 ml, 4mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at roomtemperature overnight. The reaction was quenched with 1N sodiumhydroxide (10 ml), extracted with methylene chloride (3×60 ml) andwashed with brine (3×60 ml). The organic layer was dried over anhydroussodium sulfate and filtered. Chromatography (2.5% methanol-ethylacetate) afforded 1.18 g (55%) of product as a white solid: mp 105-108°C.

[0331] The HCl salt was prepared in ethyl acetate: mp 283-285° C.Elemental analysis for C₂₇H₃₂N₄O.HCl.0.5H₂O Calc'd: C, 68.55; H, 7.03;N, 11.85 Found: C, 68.86; H, 7.29; N, 11.76

EXAMPLE 8b 5-Methoxy-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole

[0332] The trans compound was isolated at the same time as the cisisomer in 20% yield (0.43 g) as a white foam.

[0333] The HCl salt was prepared in ethyl acetate: mp 194-196° C.Elemental analysis for C₂₇H₃₂N₄O.HCl.1.5H₂O Calc'd: C, 66.65; H, 7.15;N, 11.52 Found: C, 66.65; H, 7.06; N, 11.44

EXAMPLE 9a 3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-2-methyl-1H-indole

[0334] A solution of 4-(1H-indol-3-yl)-cyclohexanone (1.44 g, 6.33mmol), 1-(indol-4-yl)piperazine (1.27 g, 6.33 mmol), sodiumtriacetoxyborohydride (1.88 g, 8.86 mmol) and acetic acid (0.76 mg, 12.6mmol) in 1,2-dichloroethane (100 ml) was allowed to stir at roomtemperature overnight. The reaction was quenched with 1N sodiumhydroxide (80 ml), extracted with methylene chloride (3×300 ml), andwashed with brine (150 ml). The organic layer was dried over anhydroussodium sulfate and filtered. The solvent was removed under vacuum toafford an off-white solid. Trituration of the solid with warm methylenechloride (80 ml) followed by filtration afforded 0.88 g of white solid.The mother liquor was concentrated and

What is claimed is:
 1. A compound of the formula:

Wherein: R₁, R₂ and R₃ are each, independently, hydrogen, halogen, CF₃,alkyl, alkoxy, MeSO₂, or together can form a 5-7 membered carbocyclic orheterocyclic ring; R₄ is hydrogen, halogen, or alkyl; R₅ is hydrogen,alkyl, alkylaryl, or aryl; R₆ is hydrogen, halogen, CF₃, CN, carbamide,or alkoxy; X₁, X₂ and X₃ are each carbon or one of X₁, X₂ or X₃ may benitrogen; Y is carbon or nitrogen; and Z is carbon or nitrogen; orpharmaceutically acceptable salts thereof.
 2. A compound as in claim 1,wherein: R₁, R₂ and R₃ are each, independently, hydrogen, halogen,alkyl, alkoxy, or together can form a 5-7 membered carbocyclic orheterocyclic ring; R₄ is hydrogen or halogen; R₅ is hydrogen, alkyl oralkylaryl; or R₆ is hydrogen, halogen, CN or alkoxy; X₁, X₂, X₃, Y and Zare each carbon; or pharmaceutically acceptable salts thereof.
 3. Acompound of claim 1 which is3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.
 4. Acompound of claim 1 which is3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.
 5. Acompound of claim 1 which is4-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.6. A compound of claim 1 which is4-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole;.7. A compound of claim 1 which is5-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.8. A compound of claim 1 which is5-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.9. A compound of claim 1 which is6-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.10. A compound of claim 1 which is6-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.11. A compound of claim 1 which is5-Bromo-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.12. A compound of claim 1 which is5-Bromo-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.13. A compound of claim 1 which is5-Chloro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.14. A compound of claim 1 which is5-Chloro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.15. A compound of claim 1 which is3-{4-[(1,4-cis)-4-(1H-indol-4-yl)-piperazinyl-1-yl]cyclohexyl}-1H-indole-5-carbonitrile.16. A compound of claim 1 which is3-{4-[(1,4-trans)-4-(1H-indol-4-yl)-piperazinyl-1-yl]cyclohexyl}-1H-indole-5-carbonitrile.17. A compound of claim 1 which is5-Methoxy-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.18. A compound of claim 1 which is5-Methoxy-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole.19. A compound of claim 1 which is3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-2-methyl-1H-indole.20. A compound of claim 1 which is3-[trans-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-2-methyl-1H-indole.21. A compound of claim 1 which is3-{(1,4-cis)-4-[4-1H-Indole-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo[2,3-b]pyridine.22. A compound of claim 1 which is3-{(1,4-trans)-4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo[2,3-b]pyridine.23. A compound of claim 1 which is6-Fluoro-1-methyl-3-{cis-4-[4-(1-methyl-1H-indol-4-yl)-1-piperazinyl]cyclohexyl}-1H-indole.24. A compound of claim 1 which is3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-methyl-1H-indole-5-carbonitrile.25. A compound of claim 1 which is3-{(1,4-trans)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-methyl-1H-indole-5-carbonitrile.26. A compound of claim 1 which is1-Ethyl-3-{(1,4-cis)-4-[4-(1H-indole-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile.27. A compound of claim 1 which is3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1-propyl-1H-indole-5-carbonitrile.28. A compound of claim 1 which is3-{(1,4-trans)-4-[4-(1H-indol-4-yl)-piperazin-4-yl]-cyclohexyl}-1-propyl-1H-indole-5-carbonitrile.29. A compound of claim 1 which is3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1-isopropyl-1H-indole-5-carbonitrile.30. A compound of claim 1 which is3-{(1,4-trans)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-isopropyl-1H-indole-5-carbonitrile.31. A compound of claim 1 which is1-Benzyl-3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile.32. A compound of claim 1 which is1-Benzyl-3-{(1,4-trans)-4-[4-(1H-indole-4-yl)-piperazin-1-yl]cyclohexyl}-1H-indole-5-5-carbonitrile.33. A compound of claim 1 which is1-Methyl-3-{(1,4-cis)-4-[4-(1-methyl-1H-indol-4-yl)-piperazine-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile.34. A compound of claim 1 which is5-Fluoro-3-{(cis)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-indole.35. A compound of claim 1 which is5-Fluoro-3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-1H-indole.36. A compound of claim 1 which is5-Fluoro-3-{(1,4-trans)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-1H-indole.37. A compound of claim 1 which is5-methoxy-3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-indole.38. A compound of claim 1 which is5-Methoxy-3-{(1,4-trans)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-indole.
 39. A compound of claim 1 whichis3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo[2,3-b]piperidin.40. A compound of claim 1 which is5-Fluoro-3-{(cis)-4-[4-(5-fluoro-2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-indole.41. A compound of claim 1 which is5-Fluoro-3-{(trans)-4-[4-(5-fluoro-2-methoxy-phenyl)-piperazin-1-yl]-cvyclohexyl}-1H-indole.42. A compound of claim 1 which is3-{(1,4-cis)-4-[4-[(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-4-fluoro-1H-indole.43. A compound of claim 1 which is3-{(1,4-cis)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-4-fluoro-1H-indole.44. A compound of claim 1 which is3-{(1,4-trans)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-5-fluoro-1H-indole.45. A compound of claim 1 which is3-{(1,4-trans)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-5-fluoro-1H-indole.46. A compound of claim 1 which is3-{(1,4-cis)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-6-fluoro-1H-indole.47. A compound of claim 1 which is3-{(1,4-trans)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-6-fluoro-1H-indole.48. A compound of claim 1 which is3-{(1,4-cis)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl]-cyclohexyl}-1H-indole-5-carbonitrile.49. A compound of claim 1 which is3-{(1,4-cis)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile.50. A compound of claim 1 which is3-{(1,4-trans)-4-(4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile.51. A compound of claim 1 which is8-{4-[(1,4-cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}quinoline.52. A compound of claim 1 which is8-{4-[(1,4-trans)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-quinoline.53. A compound of claim 1 which is8-{4-(1,4-cis)-4-[4-(5-Fluoro-1-methyl-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-quinoline.54. A compound of claim 1 which is3-[(1,4-cis)-4-(4-Quinolin-8-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-carbonitrile.55. A compound of claim 1 which is3-[(1,4-trans)-4-(4-Quinolin-8-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-carbonitrile.56. A compound of claim 1 which is1-Methyl-3-[(1,4-cis)-4-(4-quinolin-8-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-carbonitrile.57. A compound of claim 1 which is5-Fluoro-3-{(1,4-cis)-4-[4-(6-fluoro-chroman-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole.58. A compound of claim 1 which is5-Fluoro-3-{(1,4-trans)-4-[4-(6-fluoro-chroman-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole.59. A compound of claim 1 which is5-Fluoro-3-{(1,4cis)-4-[4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole.60. A compound of claim 1 which is5-Fluoro-3-{(1,4-trans)-4-[4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole.61. A compound of claim 1 which is3-{(1,4-cis)-4-[4-(5-Fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile.62. A compound of claim 1 which is3-{(1,4-trans)-4-[4-(5-Fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile.63. A compound of claim 1 which is3-{(1,4-trans)-4-[4-(5-Fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1yl]-cyclohexyl}-1-methyl-1H-indole-5-carbonitrile.64. A compound of claim 1 which is3-[(1,4-cis)-4-[4-(Benzofuran-7-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-carbonitrile.65. A compound of claim 1 which is3-[(1,4-trans)-4-[4-(Benzofuran-7-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-carbonitrile.66. A compound of claim 1 which is5-Fluoro-3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]cyclohex-1-enyl}-1H-indole.67. A compound of claim 1 which is3-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-cyclohex-1-enyl}-1H-indole-5-carbonitrile.68. A compound of claim 1 which is5-Fluoro-3-{cis-4-[4-(1H-indol-4-yl)piperazinyl]-cyclohexyl}-1-methyl-1H-indole.69. A compound of claim 1 which is3-{(1,4-cis)-4-[4-(6-Methoxy-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile.70. A pharmaceutical composition comprising a compound of the formula:

Wherein: R₁, R₂ and R₃ are each, independently, hydrogen, halogen, CF₃,alkyl, alkoxy, MeSO₂, or together can form a 5-7 membered carbocyclic orheterocyclic ring; R₄ is hydrogen, halogen, or alkyl; R₅ is hydrogen,alkyl, alkylaryl, or aryl; R₆ is hydrogen, halogen, CF₃, CN, carbamide,or alkoxy; X₁, X₂ and X₃ are each carbon or one of X₁, X₂ or X₃ may benitrogen; Y is carbon or nitrogen; and Z is carbon or nitrogen; orpharmaceutically acceptable salts thereof.
 71. A method for treatingdepression in a patient in need thereof comprising administering to saidpatient an antidepressant effective amount of a compound of the formula:

Wherein: R₁, R₂ and R₃ are each, independently, hydrogen, halogen, CF₃,alkyl, alkoxy, MeSO₂, or together can form a 5-7 membered carbocyclic orheterocyclic ring; R₄ is hydrogen, halogen, or alkyl; R₅ is hydrogen,alkyl, alkylaryl, or aryl; R₆ is hydrogen, halogen, CF₃, CN, carbamide,or alkoxy; X₁, X₂ and X₃ are each carbon or one of X₁, X₂ or X₃ may benitrogen; Y is carbon or nitrogen; and Z is carbon or nitrogen; orpharmaceutically acceptable salts thereof.